Proprotein convertase subtilisin/kexin type 9
(PCSK9), together with other members of the PCSK family of
proteases (including Furin, PC1/3, PC2, PC4, PACE4, PC5/6, PC7 and
subtilisin/kexin-isozyme-1), use serine to hydrolyze peptide bonds
(1,2). Unlike other PCSK members, PCSK9
recognizes the VFAQ amino acid motif in its internal sequence and
becomes biochemically active. Notably, mature PCSK9 does not
undergo additional proteolytic cleavage to release an active
convertase. Instead, it primarily functions as a binding protein
that regulates the degradation of its substrates/binding proteins
via the lysosomal system (3). A
previous study also found that the lysosomal system is critical for
PCSK9 degradation, in which glucagon receptor signaling plays an
important role (4). The most
prominent event for the important role of PCSK9 in human disease
was the identification of the PCSK9 variant (S127R) in familial
hypercholesterolemia, which led to the identification of its first
substrate, low-density lipoprotein receptor (LDLR) (5). Due to the critical function of LDLR in
lipoprotein trafficking, PCSK9 has become an attractive therapeutic
target for hypercholesterolemia and cardiovascular disease.
Beyond LDLR, emerging evidence suggests that PCSK9
also modulates other substrates. Given the important role of these
substrates in the hallmarks of cancer, ranging from sustained
proliferative signaling to tumor immune evasion, recent evidence
supports that PCSK9 is closely associated with tumorigenesis. For
example, Wang et al (6)
reported that PCSK9 expression is significantly upregulated in
colon cancer tissues compared to normal tissues. Furthermore,
silencing PCSK9 expression markedly reduced the tumorigenic
properties of colon cancer cells, supporting its functional role in
cancer progression. These findings suggest that PCSK9 may represent
a promising therapeutic target in oncology. In line with this,
several clinical trials have been initiated to evaluate the
efficacy of PCSK9 inhibition in patients with cancer. The present
review highlights the emerging roles of PCSK9 in regulating key
hallmarks of cancer and summarizes the latest advances in
strategies to therapeutically interfere with PCSK9 activity,
thereby underscoring its potential as a target for cancer
treatment.
The human PCSK9 gene spans 3,710 base pairs across
12 exons and encodes a protein with 692 amino acids. Unlike other
PCSK family members like Furin and PC7, PCSK9 contains only four
domains (Fig. 1), and each domain
has a distinct function (7). The
signal peptide, pro-domain and catalytic domain are conserved among
all PCSK members. Specifically, the signal peptide (amino acid
residues 1–30) is responsible for directing the protein into the
endoplasmic reticulum (ER), while the pro-domain (residues 31–152)
acts as a chaperone that enables proper folding of the catalytic
domain. The catalytic domain (residues 153–452) contains the
canonical serine proteinase catalytic triad composed of
Asp186, His226 and Ser386, which
mediates cleavage at the FAQ152 sequence within PCSK9 in
the ER. Notably, this autocleavage event causes the loss of
proteolytic activity, but it is necessary for its maturation and
subsequent secretion (8). The
Cys-His-rich domain (CHRD, residues 453–692) consists of three
tandem repeats (M1: 453–529, M2: 530–603 and M3: 604–692) that
interact with PCSK9 substrates to form a stable complex, thereby
facilitating substrate trafficking from endosomes to lysosomes.
Previous studies have indicated that partial deletion of the CHRD
severely impairs PCSK9 secretion, possibly by interfering with the
coat protein complex II component Sec24 (9), highlighting its critical role in PCSK9
maturation and secretion. In addition, other proteins such as
cytosolic adenylyl cyclase-associated protein 1 can enhance the
activity of PCSK9 by binding to the M1 and M3 repeats of the CHRD
domain (10). A mutation within
this domain mainly alters the activity of PCSK9 but not its
maturation. Conversely, certain mutations in this domain may also
promote the activity of PCSK9, thereby promoting substrate
degradation (11). However, the
precise molecular mechanism by which specific residues within the
CHRD regulate PCSK9 maturation and activity remains largely
elusive.
Similar to other PCSK family members, PCSK9 is
enriched in the trans-Golgi network, where it can be sorted into
different final destinations. PCSK9 is also localized to
endosomes/lysosomes and the cell surface. Notably, substrate
availability appears to regulate the subcellular distribution of
PCSK9. For instance, Nassoury et al (12) reported that PCSK9 is also localized
to the ER in cells lacking expression of LDLR, whereas in
LDLR-expressing cells, PCSK9 was efficiently sorted to post-ER
compartments. Further studies are still needed to elucidate the
molecular mechanisms underlying this substrate-dependent
trafficking.
Given the central role of LDLR in cholesterol and
fatty acid metabolism, PCSK9 is most abundantly expressed in the
liver, with lower expression in other tissues such as the intestine
and kidney. According to the Human Protein Atlas (https://www.proteinatlas.org/) (13), PCSK9 is also highly expressed in the
lung, colon and duodenum (Fig. 2).
This widespread tissue distribution underscores its importance in
the regulation of homeostasis. Emerging evidence further indicates
that PCSK9 regulates additional biological processes, including
adipogenesis, immune response and neurogenesis (14), thereby expanding its functional
relevance in both physiological and pathological conditions.
PCSK9 was identified in 2003 alongside variants
linked to autosomal dominant hypercholesterolemia, which highlights
the important role of PCSK9 in abnormal cholesterol metabolism.
Since then, numerous PCSK9 variants have been reported, including
Y142X and Q152H (Table I). Notably,
some of them are loss-of-function (LOF) variants, which are
associated with decreased LDL cholesterol (LDLC) levels, while
gain-of-function (GOF) variants decrease LDLR levels, thus
causing hypercholesterolemia.
Subsequent studies have elucidated how individual
PCSK9 variants impact its maturation and function. For instance,
the S462P mutation in exon 9 of the PCSK9 gene clearly impairs the
secretion of PCSK9, with the mutant protein being largely retained
in the ER, indicating that this mutation results in a LOF phenotype
(15). Structural analysis further
revealed that residue Ser462 is located immediately after the first
β-strand of the first tandem repeat of the CHRD domain. Notably,
Ser462 is one of the few highly conserved non-cysteine residues in
the CHRD domain across PCSK9 homologues, thus supporting its
important role in the function of PCSK9. Consistent with this, the
S462P mutation causes reduced LDLR degradation and can
contribute to hypocholesterolemia (15).
Among the numerous PCSK9 variants identified to
date, the most prevalent LOF variant is R46L, reported in
>100,000 individuals across diverse ethnic groups, including
British (16), Italian (17), Swedish (18), Canadian (19), Danish (20) and Spanish (21) populations. The R46L mutation is
associated with plasma lipoproteins and reduced LDLC levels, which
correlate with a decreased risk of cardiovascular diseases such as
aortic valve stenosis and ischemic heart disease (22,23).
However, a meta-analysis by Liu et al (24) reported that the PCSK9 R46L variant
may also increase the risk of diabetes mellitus, likely as a
consequence of chronically reduced LDLC levels. These contrasting
effects highlight the need for further studies to clarify the
broader impact of this variant on human health, including its
potential role in conditions beyond cardiometabolic diseases such
as cancer.
On the other hand, several GOF variants of PCSK9
have been identified across different populations. One of the most
studied is the D374Y variant, reported in Norwegian (23), British (25,26)
and Turkish (27,28) cohorts. Unlike the R46L mutation,
D374Y markedly increases circulating LDLC levels, likely through
enhanced binding affinity to LDLR and subsequent acceleration of
LDLR clearance (29). Furthermore,
the D374H variant has been described in the Portuguese population
(30). Similar to D374Y, D374H
enhances PCSK9 function and adversely affects life expectancy and
quality of life by promoting premature coronary heart disease in
patients with familial hypercholesterolemia (FH) (30). Of note, the E32K variant appears to
be unique to the Japanese population (31–33).
This variant exacerbates the phenotype of FH by elevating PCSK9
function and plasma lipid levels. Additional GOF variants,
including V4I and R496W, have also been identified in the Japanese
population (32). Despite these
insights, the precise molecular mechanisms by which different PCSK9
mutations confer GOF activity, as well as their broader
implications for human diseases beyond lipid metabolism, remain
incompletely understood and warrant investigation.
Despite PCSK9 being known for its role in regulating
plasma LDLC by binding to LDLR, accumulating evidence suggests that
it can interact with other substrates (Fig. 3), thereby promoting their
degradation. For instance, very (V)LDLR and apolipoprotein E
receptor 2 (ApoER2), which are the closest family members to LDLR,
have been shown to bind PCSK9 (34,35).
Notably, the D374Y mutation markedly enhances the degradation of
both VLDLR and ApoER2 when co-expressed in 293T or HuH7 cells,
supporting that this mutation promotes the function of PCSK9.
Furthermore, the catalytic activity of PCSK9 is not required for
the degradation of ApoER2, VLDLR or LDLR (35), indicating that the role of the
catalytic domain of mature PCSK9 warrants further
investigation.
PCSK9 has been reported to regulate the degradation
of other substrates. For instance, Demers et al (38) indicated that PCSK9 induces the
degradation of CD36 through a proteasome-sensitive mechanism in the
post-ER compartment. Consistently, knockout of PCSK9 does not alter
the mRNA levels of CD36 in hepatocytes. Furthermore, proteasome and
lysosome inhibitors block CD36 degradation, suggesting a key role
for both the ubiquitin-proteasome and autophagy-lysosome systems in
this process. In addition, PCSK9 deficiency reduces CD81 cell
surface expression, supporting a role for PCSK9 in modulating CD81
degradation (39). Notably, the LOF
mutants G236S and A239D of PCSK9 have no effect on CD81 expression,
while the GOF mutant D374Y lowers CD81 expression (40). These findings suggest that the
mutation site in PCSK9 may play an important role in determining
the fate of CD81 expression.
Recently, PCSK9 was reported to enhance the cellular
degradation of ACE2 by binding to the pro/catalytic domains of
mature PCSK9 (41), which differs
from the mechanism whereby the CHRD domain of PCSK9 is required for
LDLR degradation. Sun et al (42) reported that PCSK9 can interact with
phosphatase and tensin homolog (PTEN) and promote its lysosomal
degradation, indicating an important role of PCSK9 in the
phosphoinositide 3-kinase (PI3K)/Akt signaling pathway.
Furthermore, secreted PCSK9 facilitates the disposal of β-site
amyloid precursor protein-cleaving enzyme 1 (BACE1), a
membrane-associated protein, in a post-ER compartment (43). As expected, mutations of the
catalytic triad of PCSK9 do not impact BACE1 disposal by secreted
PCSK9. Consistently, PCSK9 knockout mice showed increased levels of
BACE1 in the brain (43). Liu et
al (44) reported that
histocompatibility 2, K1 (H2-K1) can interact with PCSK9 in tumor
cells and deletion of the M2 domain of PCSK9 completely abrogates
this interaction. Further analysis showed that overexpression of
PCSK9 reduces the expression of H2-K1, while PCSK9 deficiency
increases its expression, indicating that PCSK9 regulates the
degradation of H2-K1 (44). The
authors also found that PCSK9 reduces the expression of human
leukocyte antigen A/B/C (HLA-ABC). Notably, bafilomycin, an
inhibitor of lysosome function, increases the levels of HLA-ABC in
wild-type (WT) cells but not in PCSK9-deficient cells, suggesting a
key role for PCSK9 in regulating lysosome-mediated degradation of
HLA-ABC. Similarly, Wang et al (45) reported that PCSK9 inhibition
increases major histocompatibility complex (MHC)-II expression on
the surface of tumor cells, indicating that MHC-II could be a
potential binding protein of PCSK9. Whether PCSK9 regulates the
expression of MHC-II via lysosome-mediated degradation needs
further investigation. Additionally, future studies are needed to
identify additional PCSK9 substrates.
Cholesterol plays an important role in maintaining
cellular homeostasis and abnormal cholesterol levels are closely
associated with cancer because cancer cells require elevated
cholesterol to sustain their high metabolic demands. Multiple
prospective studies have demonstrated an association between
cholesterol levels and risk of cancer (46,47).
PCSK9, as a key regulator of cellular cholesterol homeostasis, has
been implicated in the development and progression of various types
of cancer. With the increasing identification of novel PCSK9
substrates, it has become evident that PCSK9 not only regulates
cholesterol metabolism but also contributes to other biological
processes such as immune responses (48). Therefore, PCSK9 is involved in
carcinogenesis not only by modulating cholesterol metabolism but
also by promoting aggressive features of cancer cells, including
immune evasion. Indeed, analysis of The Cancer Genome Atlas
database shows that PCSK9 is highly expressed in several types of
cancer (49). The following
subsections discuss how PCSK9 influences the hallmarks of cancer by
modulating distinct cellular components.
Proliferation is a fundamental characteristic of all
living cells and is essential for diverse cellular processes.
Unlike normal cells, cancer cells sustain uncontrolled
proliferative signaling by activating a series of signaling
cascades. Cholesterol, as an essential component of cell membranes,
is critical for maintaining cellular integrity and proliferation.
Beyond its structural role, cholesterol also serves as a precursor
for bile acids and steroid hormones such as glucocorticoids,
estrogens, progesterone, androgens and aldosterone, thereby
providing key signals for cell growth (50). Indeed, cholesterol levels are often
significantly increased in the tumor microenvironment (TME).
Epidemiological studies have consistently suggested
that high serum cholesterol levels are positively correlated with
the risk of several cancer types, including prostate (51), colorectal (52) and ovarian (53) cancer, supporting a tumor-promoting
role for cholesterol in carcinogenesis. Cholesterol exists
primarily in two forms: LDLC and high-density lipoprotein
cholesterol (HDLC). Similar to their opposing roles in
cardiovascular health, increased LDLC levels are positively
associated with cancer progression, while higher HDLC levels are
inversely correlated with the risk of cancer (54). For instance, patients with
colorectal cancer exhibiting high LDLC levels have a decreased
likelihood of disease-free survival (DFS) (55), whereas high serum HDLC levels are
associated with improved DFS (56).
Furthermore, Rodrigues Dos Santos et al (57) demonstrated that LDLC enhances the
phosphorylation of Akt and extracellular signal-regulated kinase by
activating Erb-B2 receptor tyrosine kinase 2 (HER2), thereby
promoting the proliferation of breast cancer cells. Collectively,
these findings highlight the critical role of cholesterol in
carcinogenesis by mediating proliferative signaling.
Since PCSK9 is critical for regulating LDLC levels,
which are positively associated with cell proliferation,
accumulating evidence suggests that PCSK9 acts as a key regulator
of proliferative signaling. Lupo et al (58) reported that PCSK9 induces smooth
muscle cell (SMC) proliferation in rats by activating the sterol
regulatory element-binding protein pathway and upregulating its
transcriptional targets [including 3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) reductase]. In mouse aortic vascular SMCs, silencing of
PCSK9 represses cell proliferation by decreasing the expression of
proliferating cell nuclear antigen (PCNA), Beclin1, p62 and light
chain 3 via the PI3K/Akt/mTOR signaling pathway, suggesting that
PCSK9 promotes vascular SMC proliferation independently of its
lipid-regulating function (59).
Similarly, Liu et al (60)
reported that Pep2-8 trifluoroacetate salt, a PCSK9 inhibitor,
represses the proliferation of vascular SMCs by regulating the
small nucleolar RNA host gene 16/enhancer of zeste 2 polycomb
repressive complex 2 subunit/TNF receptor-associated factor 5 axis,
further supporting an important role for PCSK9 in mediating cell
proliferation.
In human induced pluripotent stem cells (hiPSCs),
PCSK9 overexpression stimulates hiPSC proliferation. Conversely,
PCSK9 inhibition decreases cell proliferation by repressing the
phosphorylation of SMAD2 (61).
Further analysis demonstrated that PCSK9 modulates the Nodal growth
differentiation factor (NODAL) growth differentiation factor
pathway by regulating the expression of its endogenous inhibitor,
dishevelled binding antagonist of β-catenin 2, which promotes the
lysosomal degradation of TGF-β receptor 1. These findings support
that PCSK9 is an important regulator of the cell cycle in hiPSCs.
Consistent with these findings, PCSK9 knockout mice showed slower
proliferation rates and decreased migratory capacity due to
impaired G1/S phase progression of the cell cycle
(62). The authors also found that
PCSK9 overexpression in PCSK9-deficient cells partially rescues the
phenotype by downregulating the expression of α-smooth muscle
actin, MHC-II and calponin (62).
In these mice, partial hepatectomy leads to delayed expression of
PCNA, an indicator of DNA replication (63). Furthermore, induction of cyclin E
and cyclin-dependent kinase 2 is delayed in PCSK9 knockout mice
following partial hepatectomy. Sun et al (64) reported that knockdown of PCSK9
significantly reduces cell proliferation in HepG2 cells, a liver
cancer cell line. Notably, knockdown of PCSK9 has no effect on the
proliferation of B16-F1 melanoma cells, which may be attributed to
the undetectable expression of LDLR in these cells (64). In esophageal cancer cells, PCSK9
overexpression enhances cell proliferation, while PCSK9 knockdown
inhibits tumor growth (65).
Mechanistically, PCSK9 promotes the epithelial-mesenchymal
transition (EMT) by increasing C-C motif ligand 25 secretion.
However, the mechanism by which a PCSK9 substrate plays a role in
this axis remains elusive.
Accumulating evidence suggests that the apoptotic
pathway plays a critical role in mediating PCSK9-related effects on
cell proliferation. For instance, in lung adenocarcinoma cells,
PCSK9 deficiency leads to the activation of caspase-3 and
repression of the anti-apoptotic protein survivin (66). Furthermore, PCSK9 deficiency induces
ER stress by increasing the expression of glucose-regulated
proteins and enhancing the activity of protein kinase R-like ER
kinase (66). Similar mechanisms
have also been observed in neuroglioma cells. Additionally, PCSK9
deficiency increases the ratio of Bcl-2-associated X protein to
B-cell lymphoma 2 (Bax/Bcl-2), thereby promoting apoptosis by
enhancing the release of cytochrome c from mitochondria to
the cytoplasm (67). In
neuroendocrine neoplasms, knockdown of PCSK9 also suppresses tumor
growth by activating cleaved caspase-3 (68). In hepatocellular carcinoma (HCC),
PCSK9 has been reported to promote the apoptosis of cancer cells by
activating the fatty acid synthase/Bax/Bcl-2/caspase-9/caspase-3
pathway, leading to reduced proliferation of cancer cells in
vitro and in vivo (69).
Consistently, high expression of PCSK9 positively correlates with
poor prognosis in patients with HCC. By contrast, in
PCSK9-deficient mice, TNFα-mediated apoptosis predominates in
regulating melanoma tumor cell growth in the liver, a phenomenon
related to low cholesterol levels. Further analysis revealed that
TNFα regulation is independent of LDLR, as its mRNA level is
increased in mice lacking both PCSK9 and LDLR (64), indicating the involvement of other
cholesterol-related mechanisms in regulating biological processes.
In addition, PCSK9 has been reported to activate the
mitogen-activated protein kinase (MAPK) signaling pathway by
upregulating heat shock protein 70 (HSP70) expression in gastric
cancer (GC) cells, thereby suppressing apoptosis. Notably, PCSK9
does not affect cell proliferation in GC cell lines (70). Given the central role of the MAPK
signaling pathway in regulating cell proliferation, further studies
are required to elucidate why PCSK9-driven alterations in this
pathway do not impact the proliferation rate of GC cells.
Although the nanoliposomal anti-PCSK9 vaccine
efficiently reduces the plasma levels and activity of PCSK9, it
shows no significant effect on the growth of melanoma tumors in
C57BL/6 mice (71). However, the
same vaccine significantly suppresses tumor growth and prolongs the
lifespan in BALB/c mice bearing breast (72) or colon (73) tumors. These discrepancies across
cancer types suggest that both mouse strain and tumor context may
influence the efficacy of the nanoliposomal anti-PCSK9 vaccine in
regulating tumor growth, warranting further investigation.
Consistently, PCSK9 expression is lower in tumor tissues compared
with paired normal tissues, including in lung cancer and acute
myeloid leukemia (49). In
addition, previous genome-wide association studies have shown that
genetically proxied inhibition of PCSK9 is not associated with
epithelial ovarian cancer in either the Ovarian Cancer Association
Consortium dataset or the Consortium of Investigators of Modifiers
of BRCA1/2 dataset (74). In line
with these findings, PCSK9 expression in ovarian tumors does not
significantly differ from paired normal tissues (49). Taken together, these data suggest
that PCSK9 plays diverse roles in regulating cancer cell
growth.
Tumor invasion and metastasis refer to the process
by which local tumor cells spread to neighboring or distant tissues
via the circulation, representing one of the hallmarks of cancer.
It has been reported that >90% of cancer-related mortalities are
associated with tumor invasion/metastasis (75). Although the underlying mechanisms of
tumor invasion/metastasis vary across tumor types, abnormal
cholesterol metabolism plays an important role in this process. For
instance, inhibition of cholesterol biosynthesis markedly reduces
the invasive and metastatic capacity of human, rat and mouse cancer
cells (76). Cholesterol also
facilitates metastasis by enhancing the resistance of metastatic
cells to ferroptosis (77).
Furthermore, elevated plasma LDLC levels positively correlate with
the risk of lymphovascular invasion and metastasis in patients with
breast cancer (78). These studies
support the concept that dysregulated cholesterol metabolism is
closely associated with cancer invasion and metastasis through
multiple signaling pathways.
Consistent with the role of cholesterol in tumor
invasion and metastasis, PCSK9 knockout mice show reduced
metastasis of melanoma cells to the liver, accompanied by decreased
hepatic LDLC concentrations due to increased expression of LDLR.
This phenotype can be reversed by a 2-week high-cholesterol diet
(HCD) in PCSK9-deficient mice, suggesting that the PCSK9-LDLR axis
promotes tumor cell metastasis (64). In agreement with this finding, the
PCSK9-LDLR axis has also been identified as a main target of
oleuropein-mediated suppression of castration-resistant prostate
cancer metastasis (79). A previous
study reported that mechanical stretch enhances melanoma cell
invasiveness by upregulating PCSK9 and LDLR, which reduces the
cholesterol concentration in tumor cells, further implicating the
PCSK9-LDLR axis in this process (80). Similar effects have been observed in
lung cancer cells, where alirocumab, a monoclonal anti-PCSK9
antibody, increases intracellular cholesterol while decreasing
invasiveness in vitro and metastasis in vivo
(80) Furthermore, increased PCSK9
expression in lung tumors is associated with metastasis and
unfavorable patient survival (80).
Suh et al (81) showed that
PCSK9 is required for pulmonary metastasis of melanoma cells in
Ahnak knockout mice, as pulmonary metastasis of B16F10 cells is
clearly reduced in lung epithelial cell-specific tamoxifen-induced
PCSK9 conditional knockout mice. However, the precise molecular
mechanisms by which PCSK9 deficiency suppresses melanoma cell
metastasis in these models require further investigation.
By contrast, in GC, PCSK9 has been shown to enhance
invasive ability, while PCSK9 knockdown inhibits tumor metastasis
in vitro and in vivo by downregulating the HSP70-MAPK
pathway (70). Similarly, PCSK9
deficiency reduces the migration and invasion of colon cancer cells
in vitro and represses metastasis in vivo (6). Mechanistic studies further indicate
that PCSK9 can promote metastasis of colon cancer by inducing EMT
and activating the PI3K/Akt signaling pathway. Accordingly, high
expression of PCSK9 in GC tissues correlates with poor patient
survival (70). In HCC, PCSK9
expression is positively associated with microvascular invasion,
promoting vascular dissemination and metastasis of tumor cells and
contributing to poor survival outcomes (69). However, the molecular basis of
PCSK9-driven invasion and metastasis in HCC remains to be
elucidated.
PCSK9 has been identified as a key determinant of
organotropism in pancreatic ductal adenocarcinoma (PDAC) metastasis
(82). Low PCSK9 expression in
liver-avid PDAC cells enhances LDLC uptake, leading to lysosomal
cholesterol release and subsequent mTORC1 activation. Furthermore,
PCSK9-low PDAC cells convert free cholesterol into oxysterols such
as 24-hydroxycholesterol, which induces hepatocytes to synthesize
and secrete LDLC, thereby creating a tumor-supportive metabolic
niche that promotes PDAC cell colonization in the liver (82). By contrast, PCSK9-high PDAC cells
predominantly rely on de novo cholesterol biosynthesis
through the mevalonate, Bloch and Kandutsch-Russell pathways. The
expression levels of enzymes involved in cholesterol biosynthesis
are positively correlated with PCSK9 expression in human PDAC
samples. Notably, intermediates of cholesterol biosynthesis,
including 7-dehydrocholesterol and 7-dehydrodesmosterol, protect
cancer cells from ferroptosis due to their antioxidant function
(83). This adaptation allows
lung-avid PDAC cells to resist oxidative stress, supporting their
ability to metastasize to the oxygen-rich lung microenvironment
(82). Consistently, patients with
pancreatic cancer who exhibit PCSK9 expression have a significantly
shorter overall survival (OS) (84).
In a Swedish breast cancer cohort, homozygotes for
the PCSK9 rs562556 (V474I) GOF variant, exhibited a 22% risk of
distant metastatic relapse at 15 years, compared with only 2% in
non-homozygotes (85). Similar
associations have been confirmed in multiple independent breast
cancer cohorts. Of note, PCSK9 knockout mice exhibit reduced breast
cancer lung metastasis compared with WT littermates under both HCD
and regular chow conditions, whereas HCD modestly promotes lung
metastasis in WT mice. These results suggest that the
metastasis-suppressive effect of PCSK9 deficiency is not solely
mediated by LDLC reduction (85).
Further experiments found that PCSK9 promotes metastatic initiation
and proliferative competence in the lung by targeting tumor LRP1
receptors, thereby repressing the metastasis suppressors
XIAP-associated factor 1 and ubiquitin specific peptidase 18
(85). As expected, evolocumab, a
monoclonal antibody against PCSK9, suppresses breast cancer
metastasis in several mouse models. Conversely, exogenous PCSK9
treatment enhances the metastatic capacity of breast cancer cells,
while depletion of XAF1 and USP18 abolishes this pro-metastatic
effect. Altogether, these findings highlight the role of PCSK9 in
promoting cancer metastasis through diverse signaling pathways.
To sustain uncontrolled proliferation in
environments limited in oxygen and nutrients, tumor cells often
alter their metabolic programs, a phenomenon known as metabolic
reprogramming. Cholesterol is synthesized intracellularly from
acetyl-CoA through the mevalonate pathway, which involves key
enzymes such as HMG-CoA reductase. Excess cellular cholesterol is
eliminated via ABCA1 (86).
Dysregulation of this pathway can lead to abnormal cholesterol
accumulation, which contributes to multiple oncogenic processes,
including tumor initiation, migration and angiogenesis (87). PCSK9 plays a critical role in
cholesterol homeostasis and metabolic reprogramming primarily by
regulating cholesterol uptake. For instance, increased PCSK9
expression promotes colorectal carcinogenesis by repressing
cholesterol uptake, which in turn enhances cholesterol biosynthesis
and leads to the accumulation of its intermediate, geranylgeranyl
diphosphate (88). Importantly,
inhibition of PCSK9 can be combined with statins, which are HMG-CoA
reductase inhibitors, to suppress adenomatous polyposis
coli/KRAS-mutant colorectal cancer in vitro and in
vivo, providing a potential therapeutic strategy for
KRAS-mutant tumors. In prostate cancer, PCSK9 deficiency protects
cancer cells from ionizing radiation-induced cell death, likely by
regulating cholesterol levels in the TME (89). Accumulating evidence suggests that
excess cholesterol is a key regulator of radiation resistance in
tumor cells, highlighting the importance of cholesterol metabolic
reprogramming in determining therapy response (90,91).
Furthermore, PCSK9 can switch cancer cell metabolism between
cholesterol import (when PCSK9 is low) and biosynthesis (when PCSK9
is high), thus impacting the organ preference of pancreatic cancer
cells during metastasis (82). In
liver cancer, PCSK9 deficiency increases the oxygen consumption
rate and mitochondrial respiratory capacity, which allows
mitochondria to produce more ATP (92). In parallel, PCSK9 deficiency
enhances lipogenesis by increasing both lipid uptake and endogenous
synthesis. These lipid droplets can further interact with
mitochondria, forming peri-droplet mitochondria, which supply ATP
for triacylglycerol synthesis (93). Furthermore, increasing
lipid/lipoprotein uptake can enrich polyunsaturated fatty acids,
which provide the essential elements for ferroptosis by being
esterified into membrane phospholipids (94). Meanwhile, PCSK9 deficiency can
result in increased production of phosphatidylethanolamine, further
enhancing ferroptosis in tumor cells (94). Previous research has revealed that
excessive lipid peroxidation induces ferroptosis in liver cancer
cells mainly by inhibiting the anti-oxidant p62/kelch-like
ECH-associated protein 1/nuclear factor erythroid 2-related factor
2 pathway (94). Although the
precise link between PCSK9-mediated lipid dysregulation and this
pathway requires further clarification, these findings support that
PCSK9 inhibition triggers ferroptosis in both lipid-dependent and
-independent manners. Therefore, excessive lipid accumulation can
promote cell death, suggesting that PCSK9 targeting may be a
therapeutic strategy in liver cancer by regulating lipid
metabolism.
A previous Mendelian randomization study revealed
that PCSK9 LOF variants are associated not only with reduced
circulating LDLC levels but also with elevated fasting glucose and
an increased risk of type 2 diabetes, suggesting a role for PCSK9
in glucose metabolism (95).
Consistently, PCSK9 deficiency in the pancreas impairs insulin
secretion, which is attributed to increased pro-insulin content and
a reduced number of insulin granules in the readily releasable pool
(96). These findings collectively
support the involvement of PCSK9 in regulating glucose metabolism.
Given the established importance of glucose reprogramming in
carcinogenesis, further investigation is warranted to determine
whether PCSK9-related glucose metabolic reprogramming contributes
to cancer development.
The formation of new blood vessels, known as tumor
angiogenesis, supplies essential nutrients and oxygen to primary
tumor cells, and facilitates their dissemination to both adjacent
and distant organs. This process is mainly driven by various
angiogenic factors, including vascular endothelial growth factor
(VEGF) and platelet-derived growth factor, which are closely
associated with tumor progression and metastasis (97). Accumulating evidence highlights that
cholesterol metabolism also plays an important role in
angiogenesis. For instance, statins, which inhibit cholesterol
synthesis, suppress tumor angiogenesis by reducing VEGF levels,
thereby inhibiting tumor growth (98).
The role of PCSK9 in angiogenesis is increasingly
recognized. Overexpression of PCSK9 in human umbilical vein
endothelial cells (HUVECs) inhibits angiogenic processes, as
evidenced by impaired tubule formation and delayed wound healing in
functional assays. Conversely, silencing PCSK9 restores angiogenic
capacity (99). Bioinformatic
analysis further suggests that PCSK9 regulates angiogenesis through
six hub genes, namely matrix metallopeptidase 9, caspase-3, early
growth response 1, nerve growth factor receptor, left-right
determination factor 1 and NODAL. Consistently, PCSK9
overexpression represses the expression of these genes, while PCSK9
deficiency upregulates them. Furthermore, hiPSCs carrying the
PCSK9-S127R GOF mutation show altered expression of multiple genes
involved in vasculature development (99). In line with these findings,
pharmacological inhibition of PCSK9 using evolocumab enhances HUVEC
migration, and increases both tubule length and size (100). Treatment with evolocumab at 10
µg/ml also significantly increases VEGF release into the
supernatant of HUVECs, further supporting an inhibitory role of
PCSK9 in angiogenesis.
Similarly, in a colorectal cancer liver metastasis
mouse model, treatment with evolocumab alone significantly
attenuated the development of MC38 tumor cell metastasis in
vivo and prolonged survival (101). While anti-angiogenic therapy
targeting VEGF is largely ineffective in repressing metastasis in
this model, its combination with evolocumab markedly suppresses the
metastatic burden, underscoring the importance of PCSK9 in tumor
angiogenesis. Further mechanistic studies revealed that evolocumab
inhibits the expression of runt-related transcription factor 1 in
metastatic niches, thereby delaying tumor growth (101). In HCC, increased PCSK9 activity
induced by palmitoylation was shown to confer resistance to the
anti-angiogenic drug sorafenib through activation of the PI3K/Akt
signaling pathway (42). Together,
these findings highlight PCSK9 as a critical regulator of tumor
angiogenesis and a potential target for enhancing the efficacy of
existing anti-angiogenic therapies.
Immune evasion is a hallmark of cancer, which allows
tumor cells to evade immune surveillance and destruction, thereby
promoting tumor progression and metastasis (102). Accumulating evidence suggests that
aberrant cholesterol metabolism contributes to tumor immune
evasion. Indeed, elevated cholesterol levels are considered a
critical causative factor of pro-inflammatory microenvironments,
highlighting the important role of cholesterol in regulating immune
cell function (103). Tumor cells
often elevate cholesterol metabolism to generate an
immunosuppressive microenvironment, characterized by an increase in
regulatory T cells (Tregs) and M2-type macrophages. On the other
hand, inhibition of cholesterol metabolism results in a higher
abundance of CD8+ cytotoxic T cells and M1-type macrophages
(104). In addition, different
types of immune cells release cholesterol to mediate tumor
progression. For instance, tumor-associated macrophages (TAM)
produce cholesterol to regulate tumor cell metabolism and
myeloid-derived suppressor cells (MDSCs) elevate cholesterol levels
by consuming essential metabolites such as L-arginine, thereby
suppressing T-cell proliferation and activation (105). Elevated cholesterol in the TME
also impairs the migration and antigen-presenting capacity of
dendritic cells (DCs). These findings collectively underscore the
important role of cholesterol metabolism in tumor immune evasion
and progression (Fig. 4).
Accumulating evidence has established the critical
role of PCSK9 in immunological homeostasis. For instance,
disruption of PCSK9 suppresses inflammation by upregulating histone
deacetylase sirtuin 1 and inhibiting NF-κB inflammatory signaling
(107). Macchi et al
(108) reported that dysregulation
of the JAK-STAT3 signaling pathway in a chronic inflammatory
environment enhances PCSK9 expression. Another study reported that
PCSK9 mediates the proliferation, differentiation and apoptosis of
immune cells, including CD4+/CD8+ T cells, macrophages and Tregs
(109). In Tohoku Hospital
pediatrics-1-derived macrophages, stimulation with oxidized LDL
increases PCSK9 expression in a dose-dependent manner, which
subsequently induces the secretion of inflammatory cytokines such
as IL-1α, IL-6 and TNF-α via activation of the NF-κB signaling
pathway (110). Therefore, PCSK9
deficiency inhibits oxidized LDL-induced inflammation by reducing
the degradation of IκB-α, the endogenous inhibitor of NF-κB.
Consistently, when THP-1 macrophages are co-cultured with HepG2
cells overexpressing human PCSK9, macrophages exhibit elevated
expression of TNF-α and IL-1β (111). Since LDLR deficiency impairs the
PCSK9-driven inflammatory response in bone marrow-derived
macrophages, it appears that PCSK9 promotes macrophage inflammation
primarily through its classical substrate, LDLR (111). Wang et al (112) reported that PCSK9 regulates
macrophage polarization via the Toll-like receptor
(TLR4)/MyD88/NF-κB axis in an acute myocardial infarction mouse
model, with PCSK9 knockout attenuating inflammatory cell
infiltration compared with WT mice. In line with this, the
TLR4-NF-κB axis is critical for the pro-inflammatory role of PCSK9
in human macrophages (113).
However, increased expression of PCSK9 also elevates
pro-inflammatory factors, such as IL-1β and TNFα, in peritoneal
macrophages from LDLR−/− mice, indicating that PCSK9 can
regulate macrophages via LDLR-independent mechanisms (114).
During carcinogenesis, PCSK9 has been increasingly
reported to play a role in immune regulation. For example, Liu
et al (44) demonstrated
that PCSK9 promotes the lysosome-mediated degradation of MHC-I in
breast cancer, colorectal cancer and melanoma cells. Inhibition of
PCSK9 enhances the infiltration of CD8+ T, CD4+ Th and natural
killer cells, suppressing tumor progression by increasing the
production of cytokines such as IFN-γ and GzmB. These findings
indicate that PCSK9 inhibition substantially attenuates tumor
growth by counteracting cytotoxic T cell-mediated immune
evasion.
Other studies have reported that PCSK9
overexpression decreases the membrane abundance of programmed cell
death ligand 1 (PD-L1), while PCSK9 deficiency leads to PD-L1
accumulation, indicating that PCSK9 regulates PD-L1 expression via
lysosomal degradation (117).
Accordingly, PCSK9 inhibition suppresses immune evasion in
pancreatic cancer cells, thereby decreasing tumor growth and
prolonging survival (117).
Notably, PCSK9 deficiency increases PD-L1 expression more markedly
than MHC-I expression in PDAC cell lines (117). PCSK9 expression has also been
linked to limited efficacy of anti-programmed cell death 1 (PD-1)
therapy in patients with advanced non-small cell lung cancer
(NSCLC) (118). Patients with low
PCSK9 expression showed significantly longer survival than those
with high expression, underscoring the deleterious effect of PCSK9
on lung cancer progression. Consistent with this, combining a PCSK9
inhibitor with an anti-CD137 agent exerts stronger antitumor
effects in a Lewis lung cancer mouse model than either inhibitor
alone. Further analysis demonstrated an increase in cytotoxic CD8+
T cells and a reduction in Tregs in the combination group,
indicating that PCSK9 inhibition can enhance the efficacy of
immunotherapy (118). Notably,
Wang et al (119) reported
that PD-1 blockade induces upregulation of PCSK9 in a colorectal
cancer model. Therefore, PCSK9 inhibition during anti-PD-1 therapy
produces a synergistic antitumor effect in colorectal cancer by
promoting CD8+ T-cell infiltration and excluding Tregs,
highlighting its potential to improve the efficacy of anti-PD-1
immunotherapy. In melanoma, PCSK9 has been proposed as a biomarker
to predict responses to immune checkpoint blockade (ICB), such as
anti-PD-1 therapy (120), further
supporting its crucial role in tumor immune evasion. In a syngeneic
mouse model using the 4MOSC1 head and neck squamous cell carcinoma
(HNSCC) line, PCSK9 inhibition increased CD8+ T-cell infiltration
and reduced MDSCs in the TME, thereby suppressing tumor growth
(121). Furthermore, PCSK9
inhibition reinforces the antitumor effect of anti-PD-1 blockade in
this mouse model. The authors also observed that higher PCSK9
expression predicts poorer prognosis in patients with HNSCC.
Consistently, PCSK9 inhibition decreased cholesterol levels in this
model, indicating that PCSK9 regulates tumor immune evasion in an
LDLR-dependent manner. These studies imply that PCSK9 mediates
immune evasion in tumor cells via multiple protein targets.
On the other hand, a long-term high-fat diet induces
the accumulation of hepatic free cholesterol and cholesterol
crystals in PCSK9-knockout mice. This leads to enhanced formation
of crown-like structures in CD68-positive macrophages by increasing
the hepatic expression of inflammation-related genes such as TNF
and NLR family pyrin domain containing 3 (122), thereby creating a pro-inflammatory
microenvironment that promotes liver tumor growth. Despite this
systemic effect, PCSK9 expression is reduced in tumor tissues
compared with adjacent tissues in patients with HCC (123). When Huh7 cells with PCSK9
deficiency were co-cultured with THP-1 macrophages, the macrophages
showed increased expression of M2 markers such as IL-10 and
arginase 1. Conversely, overexpression of PCSK9 in MHCC97H cells
suppressed THP-1 macrophage migration and M2-like TAM polarization,
inhibiting the formation of a tumor-promoting immune
microenvironment (123). By
contrast, a different effect was observed in colon cancer models,
as the co-culture of PCSK9-deficient HCT116 and HT29 human colon
cancer cells with THP-1 macrophages reduced M2-like TAM
polarization but promoted M1-like polarization by decreasing
lactate levels, protein lactylation and macrophage migration
inhibitory factor expression (6).
Furthermore, Mei et al (85)
demonstrated that depleting tissue-resident macrophages has no
effect on breast cancer metastasis in PCSK9-knockout mice,
indicating that PCSK9 does not influence TAM polarization or
function in this context. The mechanisms underlying these
discrepant findings require further investigation, but may indicate
that the immunomodulatory effects of PCSK9 are cancer type-specific
(Fig. 4).
Given the important role of PCSK9 in carcinogenesis,
targeting PCSK9 is considered a promising therapeutic strategy for
cancer. Several clinical trials have been initiated to explore this
potential across different cancer types (Table II). For instance, plasma PCSK9
levels are associated with the severity of advanced breast cancer
(124), indicating the potential
of PCSK9 inhibitors to enhance antitumor immune responses. In
NSCLC, low serum PCSK9 levels (<95 ng/ml) predict an improved
response to anti-PD-1 therapy and are associated with improved OS
in Italian patients, when compared with those with high PCSK9
levels (>120 ng/ml) (125).
Similarly, Xie et al (126)
reported that low baseline plasma PCSK9 levels predict a favorable
prognosis in patients with advanced NSCLC treated with immune
checkpoint inhibitors (ICI), including anti-PD-1 therapy. However,
in a Chinese patient cohort, the optimal prognostic threshold for
serum PCSK9 was identified as 232.2 ng/ml. This discrepancy may be
associated with differences in ethnicity, age or sex, as serum
PCSK9 levels are known to be influenced by these factors (127). Such variations in baseline PCSK9
levels likely affect the optimal threshold for predicting ICI
efficacy, although the underlying causes remain to be elucidated.
However, these findings support the potential of combining PCSK9
inhibition with anti-PD-1 therapy in NSCLC. In fact, several
additional clinical trials are underway in NSCLC. For example,
tafolecimab, a recombinant fully humanized monoclonal antibody
against PCSK9, is currently being evaluated in combination with
ICBs in various lung cancer types, including NSCLC (NCT06385262,
NCT07014215 and NCT05553834) and SCLC (NCT07061535 and
NCT07014215). The preliminary results of these trials have not yet
been published.
Furthermore, several clinical trials are
investigating whether combining PCSK9 inhibitors with standard
treatments can improve therapeutic outcomes in patients with
advanced mismatch repair-proficient or microsatellite stable
colorectal cancer (NCT06391905, NCT06304987 and NCT06933251). In
addition, an anti-PCSK9 antibody is being evaluated in combination
with standard chemotherapy for metastatic PDAC to assess the
feasibility and acceptability of this strategy (NCT04862260). For
patients at a markedly high risk of both atherosclerotic
cardiovascular disease and cancer, another trial aims to determine
whether PCSK9 inhibition can reduce the risk of cardiovascular
mortality, recurrent unstable angina, myocardial infarction, stroke
or coronary revascularization (NCT05976893). Although these trials
are still ongoing, a retrospective study supports that PCSK9
inhibitors can clearly reduce both cardiovascular disease and
cancer mortality, thereby prolonging OS among patients with cancer
(128). However, a Mendelian
randomization study by Wang et al (129) reported that PCSK9 inhibitors could
cause divergent effects among patients with cancer. In breast and
lung cancer, PCSK9 inhibition is beneficial for patients. By
contrast, PCSK9 inhibition exacerbates clinical outcomes among
patients with gastric, hepatic and oropharyngeal cancer. Although
these ongoing clinical trials support PCSK9 as a promising
therapeutic target in cancer treatment, optimizing the benefit of
this strategy for patients with cancer will require further
clinical studies.
Since altered expression of PCSK9 has been observed
in various malignancies, elevated circulating PCSK9 can distinguish
malignant from benign lesions. In pancreatic cancer, high serum
PCSK9 levels reflect worse OS compared with low serum PCSK9 levels,
indicating the diagnostic potential of serum PCSK9 for patients
with early-stage pancreatic cancer (84). When combined with CA19-9, the
diagnostic performance of serum PCSK9 is further improved.
Similarly, the diagnostic potential of serum PCSK9 levels was
observed in women with stage III breast cancer (130). Serum PCSK9 levels positively
correlated with breast disease severity, supporting the important
role of serum PCSK9 in diagnosing breast cancer. Similarly, PCSK9
expression positively correlated with pathohistological grading and
hormone receptor status in patients with HER2-positive breast
cancer.
Beyond its diagnostic value, higher PCSK9
expression was associated with a worse response to neoadjuvant
therapy in these patients, indicating the prognostic potential of
PCSK9 in patients with cancer (131). Sun et al (132) further demonstrated the prognostic
value of PCSK9 in pan-cancer, as evidenced by its positive
correlation with immune infiltrates in the TME. Notably, serum
anti-PCSK9 antibody levels reflected improved OS prognosis after
surgery in patients with esophageal cancer (133). These findings support that PCSK9
could be a biomarker for cancer diagnosis and prognosis. Besides,
in patients with NSCLC treated with PD-1 immunotherapy, Wood et
al (134) found that patients
with higher PCSK9 levels had worse progression-free survival
compared with those with low PCSK9 levels, a finding that could
result from increased CD8+ and GzmB+
CD8+ T cells and reduced Tregs (118), supporting that serum PCSK9 levels
could be a biomarker for PD-1 immunotherapy response among patients
with NSCLC. Consistently, the combination of PCSK9 inhibitors with
PD-1 inhibitors resulted in stronger antitumor activity compared
with PD-1 inhibitors alone in pancreatic cancer (117). A previous study also reported that
PCSK9 deficiency caused downregulation of Nrf2, which was
associated with conferring cellular resistance to chemotherapeutic
drugs such as sorafenib in liver cancer (94), suggesting an indirect connection
between PCSK9 expression and sorafenib resistance. Sun et al
(42) further reported that PCSK9
palmitoylation enhances the interaction between PCSK9 and PTEN,
which induces PTEN to enter lysosomes for degradation and Akt
activation, decreasing the antitumor effects of sorafenib in HCC.
Therefore, PCSK9 is a potential biomarker for sorafenib treatment
response. However, whether PCSK9 can be a biomarker for other
cancer treatments such as chemotherapy and radiotherapy still needs
to be further evaluated.
PCSK9, the most recently identified member of the
PCSK family, is currently the only family member with a clinically
approved therapeutic application, namely in the treatment of
hypercholesterolemia. This is based on its canonical role in
mediating the lysosomal degradation of LDLR. However, accumulating
evidence suggests that PCSK9 also targets other substrates,
including MHC-I and LRP1, thereby implicating it in diverse
pathological processes such as sepsis (135) and Alzheimer's disease (136). Whether PCSK9 exhibits
substrate-binding preferences that dictate its functional roles in
different disease contexts remains elusive, but represents a
critical question for understanding its broader physiological
importance. For instance, while PCSK9 deficiency has been reported
to suppress tumor growth by preventing MHC-I degradation (44), it remains unclear why PCSK9 does not
concurrently regulate LDLR degradation in the same tumor cells.
Therefore, systematic identification of new PCSK9 substrates across
the human proteome will be essential to fully elucidate its
mechanistic contributions to both physiological and pathological
processes, which would advance the current understanding of its
role in cancer.
Carcinogenesis is a multistep process driven by
several abnormal physiological features, known as the hallmarks of
cancer, which provide ideal targets for therapy. The present review
highlighted the role of PCSK9 in five key hallmarks of cancer,
including sustaining proliferative signaling, invasion/metastasis,
metabolic reprogramming, angiogenesis and immune evasion. However,
cancer cells exhibit additional hallmarks, such as non-mutational
epigenetic reprogramming and polymorphic microbiomes (137), and whether PCSK9 contributes to
these features remains to be determined. Although PCSK9 may not
directly regulate every hallmark, it influences the degradation of
>10 proteins, some of which are critically involved in these
processes. PTEN serves as a prime example, as its deletion not only
promotes epigenetic reprogramming in prostate cancer (138) but also disrupts gut microbiome
homeostasis (139). Determining
whether PCSK9 regulates these carcinogenic properties through such
substrates will be essential for a comprehensive understanding of
its role in tumor biology. It should also be noted that a single
PCSK9 substrate can influence multiple hallmarks. For instance,
LDLR, through cholesterol modulation, not only promotes cell
proliferation but also regulates angiogenesis (87,140).
Thus, dissecting the specific contributions of PCSK9 substrates to
different hallmarks of cancer will be crucial to unravel the
multifaceted role of PCSK9 in carcinogenesis.
The authors would like to thank Ms. Qiqi Xu
(Department of Nursing, Daping Hospital, Army Medical University)
for inspiration and discussion. The figures were created with
BioRender (biorender.com).
The study was supported by grants from the Natural Science
Foundation of Chongqing (grant no. CSTB2025NSCQ-GPX0091) and
Military Special Program for Nursing Innovation and Cultivation
(grant no. 2023HL001). This work was also funded by grant no.
CNS2024-154532 from the Ministerio de Ciencia, Innovación y
Universidades/Agencia Estatal de
Investigación/10.13039/501100011033.
Not applicable.
LT conceived the study and wrote the manuscript
with contributions from ZH, SY and YZ. The figures of the
manuscript were conceived and designed by ZH. BRM and YX
contributed to designing the study, writing/revising the
manuscript, acquiring the funding and supervision. Data
authentication is not applicable. All authors have read and
approved the final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
|
1
|
Siegfried G, Liu Y, He Z, Evrard S,
Badiola I, Pernot S, Creemers JWM and Khatib AM: Furin-like enzyme
dependency in KRAS-mutant colorectal cancer as a target for
personalized treatment strategies. Biochim Biophys Acta Rev Cancer.
1881:1896202026. View Article : Google Scholar : PubMed/NCBI
|
|
2
|
He Z, Khatib AM and Creemers JWM: The
proprotein convertase furin in cancer: More than an oncogene.
Oncogene. 41:1252–1262. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
3
|
Seidah NG and Prat A: The biology and
therapeutic targeting of the proprotein convertases. Nat Rev Drug
Discov. 11:367–383. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
4
|
Spolitu S, Dai W, Zadroga JA and Ozcan L:
Proprotein convertase subtilisin/kexin type 9 and lipid metabolism.
Curr Opin Lipidol. 30:186–191. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
5
|
Abifadel M, Varret M, Rabès JP, Allard D,
Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich
D, et al: Mutations in PCSK9 cause autosomal dominant
hypercholesterolemia. Nat Genet. 34:154–156. 2003. View Article : Google Scholar : PubMed/NCBI
|
|
6
|
Wang L, Li S, Luo H, Lu Q and Yu S: PCSK9
promotes the progression and metastasis of colon cancer cells
through regulation of EMT and PI3K/AKT signaling in tumor cells and
phenotypic polarization of macrophages. J Exp Clin Cancer Res.
41:3032022. View Article : Google Scholar : PubMed/NCBI
|
|
7
|
Xia XD, Peng ZS, Gu HM, Wang M, Wang GQ
and Zhang DW: Regulation of PCSK9 expression and function:
Mechanisms and therapeutic implications. Front Cardiovasc Med.
8:7640382021. View Article : Google Scholar : PubMed/NCBI
|
|
8
|
Cunningham D, Danley DE, Geoghegan KF,
Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp
JS, Hoth LR, et al: Structural and biophysical studies of PCSK9 and
its mutants linked to familial hypercholesterolemia. Nat Struct Mol
Biol. 14:413–419. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
9
|
Deng SJ, Shen Y, Gu HM, Guo S, Wu SR and
Zhang DW: The role of the C-terminal domain of PCSK9 and SEC24
isoforms in PCSK9 secretion. Biochim Biophys Acta Mol Cell Biol
Lipids. 1865:1586602020. View Article : Google Scholar : PubMed/NCBI
|
|
10
|
Fruchart Gaillard C, Ouadda ABD, Ciccone
L, Girard E, Mikaeeli S, Evagelidis A, Le Dévéhat M, Susan-Resiga
D, Lajeunesse EC, Nozach H, et al: Molecular interactions of PCSK9
with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation
of LDLR levels. Mol Metab. 67:1016622023. View Article : Google Scholar : PubMed/NCBI
|
|
11
|
Sánchez-Hernández RM, Di Taranto MD,
Benito-Vicente A, Uribe KB, Lamiquiz-Moneo I, Larrea-Sebal A,
Jebari S, Galicia-Garcia U, Nóvoa FJ, Boronat M, et al: The
Arg499His gain-of-function mutation in the C-terminal domain of
PCSK9. Atherosclerosis. 289:162–172. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
12
|
Nassoury N, Blasiole DA, Tebon Oler A,
Benjannet S, Hamelin J, Poupon V, McPherson PS, Attie AD, Prat A
and Seidah NG: The cellular trafficking of the secretory proprotein
convertase PCSK9 and its dependence on the LDLR. Traffic.
8:718–732. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
13
|
Uhlen M, Karlsson MJ, Zhong W, Tebani A,
Pou C, Mikes J, Lakshmikanth T, Forsström B, Edfors F, Odeberg J,
et al: A genome-wide transcriptomic analysis of protein-coding
genes in human blood cells. Science. 366:eaax91982019. View Article : Google Scholar : PubMed/NCBI
|
|
14
|
Momtazi-Borojeni AA, Sabouri-Rad S, Gotto
AM, Pirro M, Banach M, Awan Z, Barreto GE and Sahebkar A: PCSK9 and
inflammation: A review of experimental and clinical evidence. Eur
Heart J Cardiovasc Pharmacother. 5:237–245. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
15
|
Cameron J, Holla ØL, Laerdahl JK, Kulseth
MA, Berge KE and Leren TP: Mutation S462P in the PCSK9 gene reduces
secretion of mutant PCSK9 without affecting the autocatalytic
cleavage. Atherosclerosis. 203:161–165. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
16
|
Guo Q, Feng X and Zhou Y: PCSK9 variants
in familial hypercholesterolemia: A comprehensive synopsis. Front
Genet. 11:10202020. View Article : Google Scholar : PubMed/NCBI
|
|
17
|
Guella I, Asselta R, Ardissino D, Merlini
PA, Peyvandi F, Kathiresan S, Mannucci PM, Tubaro M and Duga S:
Effects of PCSK9 genetic variants on plasma LDL cholesterol levels
and risk of premature myocardial infarction in the Italian
population. J Lipid Res. 51:3342–3349. 2010. View Article : Google Scholar : PubMed/NCBI
|
|
18
|
Chernogubova E, Strawbridge R, Mahdessian
H, Mälarstig A, Krapivner S, Gigante B, Hellénius ML, de Faire U,
Franco-Cereceda A, Syvänen AC, et al: Common and low-frequency
genetic variants in the pcsk9 locus influence circulating PCSK9
levels. Arterioscler Thromb Vasc Biol. 32:1526–1534. 2012.
View Article : Google Scholar : PubMed/NCBI
|
|
19
|
Saavedra YGL, Dufour R, Davignon J and
Baass A: PCSK9 R46L, lower LDL, and cardiovascular disease risk in
familial hypercholesterolemia: A cross-sectional cohort study.
Arterioscler Thromb Vasc Biol. 34:2700–2705. 2014. View Article : Google Scholar : PubMed/NCBI
|
|
20
|
Langsted A, Nordestgaard BG, Benn M,
Tybjærg-Hansen A and Kamstrup PR: PCSK9 R46L loss-of-function
mutation reduces lipoprotein(a), LDL cholesterol, and risk of
aortic valve stenosis. J Clin Endocrinol Metab. 101:3281–3287.
2016. View Article : Google Scholar : PubMed/NCBI
|
|
21
|
Mostaza JM, Lahoz C, Salinero-Fort MA, de
Dios O, Castillo E, González-Alegre T, García-Iglesias F, Estirado
E, Laguna F, Sabín C, et al: R46L polymorphism in the PCSK9 gene:
Relationship to lipid levels, subclinical vascular disease, and
erectile dysfunction. J Clin Lipidol. 12:1039–1046.e3. 2018.
View Article : Google Scholar : PubMed/NCBI
|
|
22
|
Benn M, Nordestgaard BG, Grande P, Schnohr
P and Tybjaerg-Hansen A: PCSK9 R46L, low-density lipoprotein
cholesterol levels, and risk of ischemic heart disease: 3
independent studies and meta-analyses. J Am Coll Cardiol.
55:2833–2842. 2010. View Article : Google Scholar : PubMed/NCBI
|
|
23
|
Da Dalt L, Castiglioni L, Baragetti A,
Audano M, Svecla M, Bonacina F, Pedretti S, Uboldi P, Benzoni P,
Giannetti F, et al: PCSK9 deficiency rewires heart metabolism and
drives heart failure with preserved ejection fraction. Eur Heart J.
42:3078–3090. 2021. View Article : Google Scholar : PubMed/NCBI
|
|
24
|
Liu S, Wan J, Wang D, Yang Y, Fang J, Luo
T, Liang D, Hu J, Hou J and Wang P: Effect of the PCSK9 R46L
genetic variant on plasma insulin and glucose levels, risk of
diabetes mellitus and cardiovascular disease: A meta-analysis. Nutr
Metab Cardiovasc Dis. 34:1339–1351. 2024. View Article : Google Scholar : PubMed/NCBI
|
|
25
|
Taylor A, Tabrah S, Wang D, Sozen M,
Duxbury N, Whittall R, Humphries SE and Norbury G: Multiplex ARMS
analysis to detect 13 common mutations in familial
hypercholesterolaemia. Clin Genet. 71:561–568. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
26
|
Humphries SE, Whittall RA, Hubbart CS,
Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M,
Durrington PN, et al: Genetic causes of familial
hypercholesterolaemia in patients in the UK: Relation to plasma
lipid levels and coronary heart disease risk. J Med Genet.
43:943–949. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
27
|
Kaya E, Kayıkçıoğlu M, Tetik Vardarlı A,
Eroğlu Z, Payzın S and Can L: PCSK 9 gain-of-function mutations
(R496W and D374Y) and clinical cardiovascular characteristics in a
cohort of Turkish patients with familial hypercholesterolemia.
Anatol J Cardiol. 18:266–272. 2017.PubMed/NCBI
|
|
28
|
Eroğlu Z, Tetik Vardarlı A, Düzgün Z,
Gündüz C, Bozok Çetintaş V and Kayıkçıoğlu M: Case-control study on
PCSK9 R496W (rs374603772) and D374Y (rs137852912) mutations in
Turkish patients with primary dyslipidemia. Anatol J Cardiol.
19:334–340. 2018.PubMed/NCBI
|
|
29
|
Humphries SE, Neely RDG, Whittall RA,
Troutt JS, Konrad RJ, Scartezini M, Li KW, Cooper JA, Acharya J and
Neil A: Healthy individuals carrying the PCSK9 p.R46L variant and
familial hypercholesterolemia patients carrying PCSK9 p.D374Y
exhibit lower plasma concentrations of PCSK9. Clin Chem.
55:2153–2161. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
30
|
Bourbon M, Alves AC, Medeiros AM, Silva S
and Soutar AK: Familial hypercholesterolaemia in Portugal.
Atherosclerosis. 196:633–642. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
31
|
Mabuchi H, Nohara A, Noguchi T, Kobayashi
J, Kawashiri MA, Inoue T, Mori M, Tada H, Nakanishi C, Yagi K, et
al: Genotypic and phenotypic features in homozygous familial
hypercholesterolemia caused by proprotein convertase
subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.
Atherosclerosis. 236:54–61. 2014. View Article : Google Scholar : PubMed/NCBI
|
|
32
|
Ohta N, Hori M, Takahashi A, Ogura M,
Makino H, Tamanaha T, Fujiyama H, Miyamoto Y and Harada-Shiba M:
Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR
mutations modifies the phenotype of familial hypercholesterolemia.
J Clin Lipidol. 10:547–555.e5. 2016. View Article : Google Scholar : PubMed/NCBI
|
|
33
|
Noguchi T, Katsuda S, Kawashiri MA, Tada
H, Nohara A, Inazu A, Yamagishi M, Kobayashi J and Mabuchi H: The
E32K variant of PCSK9 exacerbates the phenotype of familial
hypercholesterolaemia by increasing PCSK9 function and
concentration in the circulation. Atherosclerosis. 210:166–172.
2010. View Article : Google Scholar : PubMed/NCBI
|
|
34
|
Barcena ML, Estepa M, Marx L, Breiter A,
Haritonow N and Stawowy P: The impact of the PCSK-9/VLDL-receptor
axis on inflammatory cell polarization. Cytokine. 161:1560772023.
View Article : Google Scholar : PubMed/NCBI
|
|
35
|
Poirier S, Mayer G, Benjannet S, Bergeron
E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A and Seidah
NG: The proprotein convertase PCSK9 induces the degradation of low
density lipoprotein receptor (LDLR) and its closest family members
VLDLR and ApoER2. J Biol Chem. 283:2363–2372. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
36
|
Canuel M, Sun X, Asselin MC, Paramithiotis
E, Prat A and Seidah NG: Proprotein convertase Subtilisin/Kexin
type 9 (PCSK9) can mediate degradation of the low density
lipoprotein receptor-related protein 1 (LRP-1). PLoS One.
8:e641452013. View Article : Google Scholar : PubMed/NCBI
|
|
37
|
Badimon L, Luquero A, Crespo J, Peña E and
Borrell-Pages M: PCSK9 and LRP5 in macrophage lipid internalization
and inflammation. Cardiovasc Res. 117:2054–2068. 2021. View Article : Google Scholar : PubMed/NCBI
|
|
38
|
Demers A, Samami S, Lauzier B, Des Rosiers
C, Sock ETN, Ong H and Mayer G: PCSK9 induces CD36 degradation and
affects Long-chain fatty acid uptake and triglyceride metabolism in
adipocytes and in mouse liver. Arterioscler Thromb Vasc Biol.
35:2517–2525. 2015. View Article : Google Scholar : PubMed/NCBI
|
|
39
|
Labont́e P, Begley S, Gúevin C, Asselin
MC, Nassoury N, Mayer G, Prat A and Seidah NG: PCSK9 impedes
hepatitis C virus infection in vitro and modulates liver CD81
expression. Hepatology. 50:17–24. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
40
|
Le QT, Blanchet M, Seidah NG and Labonté
P: Plasma membrane tetraspanin CD81 complexes with proprotein
convertase subtilisin/kexin type 9 (PCSK9) and low density
lipoprotein receptor (LDLR), and Its levels are reduced by PCSK9. J
Biol Chem. 290:23385–23400. 2015. View Article : Google Scholar : PubMed/NCBI
|
|
41
|
Essalmani R, Andréo U, Evagelidis A, Le
Dévéhat M, Pereira Ramos OH, Fruchart Gaillard C, Susan-Resiga D,
Cohen ÉA and Seidah NG: SKI-1/S1P Facilitates SARS-CoV-2 spike
induced Cell-to-Cell fusion via activation of SREBP-2 and
Metalloproteases, Whereas PCSK9 enhances the degradation of ACE2.
Viruses. 15:3602023. View Article : Google Scholar : PubMed/NCBI
|
|
42
|
Sun Y, Zhang H, Meng J, Guo F, Ren D, Wu H
and Jin X: S-palmitoylation of PCSK9 induces sorafenib resistance
in liver cancer by activating the PI3K/AKT pathway. Cell Rep.
40:1111942022. View Article : Google Scholar : PubMed/NCBI
|
|
43
|
Jonas MC, Costantini C and Puglielli L:
PCSK9 is required for the disposal of non-acetylated intermediates
of the nascent membrane protein BACE1. EMBO Rep. 9:916–922. 2008.
View Article : Google Scholar : PubMed/NCBI
|
|
44
|
Liu X, Bao X, Hu M, Chang H, Jiao M, Cheng
J, Xie L, Huang Q, Li F and Li CY: Inhibition of PCSK9 potentiates
immune checkpoint therapy for cancer. Nature. 588:693–698. 2020.
View Article : Google Scholar : PubMed/NCBI
|
|
45
|
Wang H, Zhang X, Zhang Y, Shi T, Zhang Y,
Song X, Liu B, Wang Y and Wei J: Targeting PCSK9 to upregulate
MHC-II on the surface of tumor cells in tumor immunotherapy. BMC
Cancer. 24:4452024. View Article : Google Scholar : PubMed/NCBI
|
|
46
|
Lin Q, Liu W, Xu S and Sun L: Associations
of preoperative serum high-density lipoprotein cholesterol and
low-density lipoprotein cholesterol levels with the prognosis of
ovarian cancer. Arch Gynecol Obstet. 305:683–691. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
47
|
Gu J, Zhu N, Li HF, Zhao TJ, Zhang CJ,
Liao DF and Qin L: Cholesterol homeostasis and cancer: A new
perspective on the low-density lipoprotein receptor. Cell Oncol.
45:709–728. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
48
|
Seidah NG and Garçon D: Expanding biology
of PCSK9: Roles in atherosclerosis and beyond. Curr Atheroscler
Rep. 24:821–830. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
49
|
Tang Z, Kang B, Li C, Chen T and Zhang Z:
GEPIA2: An enhanced web server for large-scale expression profiling
and interactive analysis. Nucleic Acids Res. 47:W556–W560. 2019.
View Article : Google Scholar : PubMed/NCBI
|
|
50
|
Liu X, Lv M, Zhang W and Zhan Q:
Dysregulation of cholesterol metabolism in cancer progression.
Oncogene. 42:3289–3302. 2023. View Article : Google Scholar : PubMed/NCBI
|
|
51
|
Shafique K, McLoone P, Qureshi K, Leung H,
Hart C and Morrison DS: Cholesterol and the risk of grade-specific
prostate cancer incidence: Evidence from two large prospective
cohort studies with up to 37 years' follow up. BMC Cancer.
12:252012. View Article : Google Scholar : PubMed/NCBI
|
|
52
|
Lorestani P, Faghihkhorasani F, Saffar H,
Darabi B, Tavakoli Y, Lorestani AM, Ghiasi M and Jazi K: The impact
of cholecystectomy on colorectal cancer risk: A comprehensive
review on risk factors and the association. Curr Gastroenterol Rep.
27:592025. View Article : Google Scholar : PubMed/NCBI
|
|
53
|
Zhang D, Xi Y and Feng Y: Ovarian cancer
risk in relation to blood lipid levels and hyperlipidemia: A
systematic review and meta-analysis of observational epidemiologic
studies. Eur J Cancer Prev. 30:161–170. 2021. View Article : Google Scholar : PubMed/NCBI
|
|
54
|
Patel KK and Kashfi K: Lipoproteins and
cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs.
Biochem Pharmacol. 196:1146542022. View Article : Google Scholar : PubMed/NCBI
|
|
55
|
Murai T: Cholesterol lowering: Role in
cancer prevention and treatment. Biol Chem. 396:1–11. 2015.
View Article : Google Scholar : PubMed/NCBI
|
|
56
|
Wang Y, Sun XQ, Lin HC, Wang DS, Wang ZQ,
Shao Q, Wang FH, Yan SM, Liang JY, Zeng ZL, et al: Correlation
between immune signature and high-density lipoprotein cholesterol
level in stage II/III colorectal cancer. Cancer Med. 8:1209–1217.
2019. View Article : Google Scholar : PubMed/NCBI
|
|
57
|
Rodrigues Dos Santos C, Domingues G,
Matias I, Matos J, Fonseca I, De Almeida JM and Dias S:
LDL-cholesterol signaling induces breast cancer proliferation and
invasion. Lipids Health Dis. 13:162014. View Article : Google Scholar : PubMed/NCBI
|
|
58
|
Lupo MG, Marchianò S, Adorni MP, Zimetti
F, Ruscica M, Greco MF, Corsini A and Ferri N: Pcsk9 induces rat
smooth muscle cell proliferation and counteracts the pleiotropic
effects of simvastatin. Int J Mol Sci. 22:41142021. View Article : Google Scholar : PubMed/NCBI
|
|
59
|
Zhang Q, Miao M, Cao S, Liu D, Cao Z, Bai
X, Yin Y, Jin S, Dong L and Zheng M: PCSK9 promotes vascular
neointimal hyperplasia through non-lipid regulation of vascular
smooth muscle cell proliferation, migration, and autophagy. Biochem
Biophys Res Commun. 742:1510812025. View Article : Google Scholar : PubMed/NCBI
|
|
60
|
Liu Y, Zhao Y, Feng P and Jiang H: PCSK9
inhibitor attenuates atherosclerosis by regulating
SNHG16/EZH2/TRAF5-mediated VSMC proliferation, migration, and foam
cell formation. Cell Biol Int. 47:1267–1280. 2023. View Article : Google Scholar : PubMed/NCBI
|
|
61
|
Roudaut M, Idriss S, Caillaud A, Girardeau
A, Rimbert A, Champon B, David A, Lévêque A, Arnaud L, Pichelin M,
et al: PCSK9 regulates the NODAL signaling pathway and cellular
proliferation in hiPSCs. Stem Cell Reports. 16:2958–2972. 2021.
View Article : Google Scholar : PubMed/NCBI
|
|
62
|
Ferri N, Marchianò S, Tibolla G, Baetta R,
Dhyani A, Ruscica M, Uboldi P, Catapano AL and Corsini A: PCSK9
knock-out mice are protected from neointimal formation in response
to perivascular carotid collar placement. Atherosclerosis.
253:214–224. 2016. View Article : Google Scholar : PubMed/NCBI
|
|
63
|
Zaid A, Roubtsova A, Essalmani R,
Marcinkiewicz J, Chamberland A, Hamelin J, Tremblay M, Jacques H,
Jin W, Davignon J, et al: Proprotein convertase subtilisin/kexin
type 9 (PCSK9): Hepatocyte-specific low-density lipoprotein
receptor degradation and critical role in mouse liver regeneration.
Hepatology. 48:646–654. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
64
|
Sun X, Essalmani R, Day R, Khatib AM,
Seidah NG and Prat A: Proprotein convertase subtilisin/kexin type 9
deficiency reduces melanoma metastasis in liver. Neoplasia.
14:1122–1131. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
65
|
Wang H, Guo Q, Wang M, Liu C and Tian Z:
PCSK9 promotes tumor cell proliferation and migration by
facilitating CCL25 secretion in esophageal squamous cell carcinoma.
Oncol Lett. 26:5002023. View Article : Google Scholar : PubMed/NCBI
|
|
66
|
Xu X, Cui Y, Cao L, Zhang Y, Yin Y and Hu
X: PCSK9 regulates apoptosis in human lung adenocarcinoma A549
cells via endoplasmic reticulum stress and mitochondrial signaling
pathways. Exp Ther Med. 13:1993–1999. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
67
|
Piao MX, Bai JW, Zhang PF and Zhang YZ:
PCSK9 regulates apoptosis in human neuroglioma u251 cells via
mitochondrial signaling pathways. Int J Clin Exp Pathol.
8:2787–2794. 2015.PubMed/NCBI
|
|
68
|
Bai J, Na H, Hua X, Wei Y, Ye T, Zhang Y,
Jian G, Zeng W, Yan L and Tang Q: A retrospective study of NENs and
miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9
inhibition. Oncotarget. 8:6929–6939. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
69
|
Zhang SZ, Zhu XD, Feng LH, Li XL, Liu XF,
Sun HC and Tang ZY: PCSK9 promotes tumor growth by inhibiting tumor
cell apoptosis in hepatocellular carcinoma. Exp Hematol Oncol.
10:252021. View Article : Google Scholar : PubMed/NCBI
|
|
70
|
Xu B, Li S, Fang Y, Zou Y, Song D, Zhang S
and Cai Y: Proprotein convertase subtilisin/kexin type 9 promotes
gastric cancer metastasis and suppresses apoptosis by facilitating
MAPK signaling pathway through HSP70 Up-regulation. Front Oncol.
10:6096632021. View Article : Google Scholar : PubMed/NCBI
|
|
71
|
Momtazi-Borojeni AA, Nik ME, Jaafari MR,
Banach M and Sahebkar A: Effects of immunisation against PCSK9 in
mice bearing melanoma. Arch Med Sci. 16:189–199. 2020. View Article : Google Scholar : PubMed/NCBI
|
|
72
|
Momtazi-Borojeni AA, Ebrahimi Nik M, Reza
Jaafari M, Banach M and Sahebkar A: Effects of immunization against
PCSK9 in an experimental model of breast cancer. Arch Med Sci.
15:570–579. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
73
|
Momtazi-Borojeni AA, Nik ME, Jaafari MR,
Banach M and Sahebkar A: Potential anti-tumor effect of a
nanoliposomal antiPCSK9 vaccine in mice bearing colorectal cancer.
Arch Med Sci. 15:559–569. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
74
|
Yarmolinsky J, Bull CJ, Vincent EE,
Robinson J, Walther A, Smith GD, Lewis SJ, Relton CL and Martin RM:
Association between genetically proxied inhibition of HMG-CoA
reductase and epithelial ovarian cancer. JAMA. 323:646–655. 2020.
View Article : Google Scholar : PubMed/NCBI
|
|
75
|
Li Y, Liu F, Cai Q, Deng L, Ouyang Q,
Zhang XHF and Zheng J: Invasion and metastasis in cancer: Molecular
insights and therapeutic targets. Signal Transduct Target Ther.
10:572025. View Article : Google Scholar : PubMed/NCBI
|
|
76
|
Matar P, Rozados VR, Binda MM, Roggero EA,
Bonfil RD and Scharovsky OG: Inhibitory effect of Lovastatin on
spontaneous metastases derived from a rat lymphoma. Clin Exp
Metastasis. 17:19–25. 1999. View Article : Google Scholar : PubMed/NCBI
|
|
77
|
Kusama T, Mukai M, Akedo H, Inoue M,
Nakamura H, Iwasaki T and Tatsuta M:
3-Hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce
human pancreatic cancer cell invasion and metastasis.
Gastroenterology. 122:308–317. 2002. View Article : Google Scholar : PubMed/NCBI
|
|
78
|
Rodrigues dos Santos C, Fonseca I, Dias S
and de Almeida JCM: Plasma level of LDL-cholesterol at diagnosis is
a predictor factor of breast tumor progression. BMC Cancer.
14:1322014. View Article : Google Scholar : PubMed/NCBI
|
|
79
|
Ahmed NA, Mohyeldin MM, Ebrahim HY,
McGehee OC, Tarun MTI and El Sayed KA: (−)-Oleuropein as a novel
metastatic Castration-resistant prostate cancer progression and
recurrence suppressor via targeting PCSK9-LDLR axis. Nutrients.
17:14452025. View Article : Google Scholar : PubMed/NCBI
|
|
80
|
López-Alonso I, López-Martínez C,
Martín-Vicente P, Amado-Rodríguez L, González-López A,
Mayordomo-Colunga J, Del Busto C, Bernal M, Crespo I, Astudillo A,
et al: Mechanical ventilation promotes lung tumour spread by
modulation of cholesterol cell content. Eur Respir J.
60:21014702022. View Article : Google Scholar : PubMed/NCBI
|
|
81
|
Suh JM, Son Y, Yoo JY, Goh Y, Seidah NG,
Lee S and Bae YS: Proprotein convertase subtilisin/kexin Type 9 is
required for Ahnak-mediated metastasis of melanoma into lung
epithelial cells. Neoplasia. 23:993–1001. 2021. View Article : Google Scholar : PubMed/NCBI
|
|
82
|
Rademaker G, Hernandez GA, Seo Y, Dahal S,
Miller-Phillips L, Li AL, Peng XL, Luan C, Qiu L, Liegeois MA, et
al: PCSK9 drives sterol-dependent metastatic organ choice in
pancreatic cancer. Nature. 643:1381–1390. 2025. View Article : Google Scholar : PubMed/NCBI
|
|
83
|
Freitas FP, Alborzinia H, dos Santos AF,
Nepachalovich P, Pedrera L, Zilka O, Inague A, Klein C, Aroua N,
Kaushal K, et al: 7-Dehydrocholesterol is an endogenous suppressor
of ferroptosis. Nature. 626:401–410. 2024. View Article : Google Scholar : PubMed/NCBI
|
|
84
|
Xu Y, Xu Y, Yang Y, Zhang Z, Xiong Q and
Zhu Q: Serum PCSK9 is a novel serological biomarker for the
diagnosis and prognosis of pancreatic cancer. PeerJ. 12:e180182024.
View Article : Google Scholar : PubMed/NCBI
|
|
85
|
Mei W, Faraj Tabrizi S, Godina C, Lovisa
AF, Isaksson K, Jernström H and Tavazoie SF: A commonly inherited
human PCSK9 germline variant drives breast cancer metastasis via
LRP1 receptor. Cell. 188:371–389.e28. 2025. View Article : Google Scholar : PubMed/NCBI
|
|
86
|
Jin HR, Wang J, Wang ZJ, Xi MJ, Xia BH,
Deng K and Yang JL: Lipid metabolic reprogramming in tumor
microenvironment: From mechanisms to therapeutics. J Hematol Oncol.
16:1032023. View Article : Google Scholar : PubMed/NCBI
|
|
87
|
Jiang W, Jin WL and Xu AM: Cholesterol
metabolism in tumor microenvironment: Cancer hallmarks and
therapeutic opportunities. Int J Biol Sci. 20:2044–2071. 2024.
View Article : Google Scholar : PubMed/NCBI
|
|
88
|
Wong CC, Wu JL, Ji F, Kang W, Bian X, Chen
H, Chan LS, Luk STY, Tong S, Xu J, et al: The cholesterol uptake
regulator PCSK9 promotes and is a therapeutic target in
APC/KRAS-mutant colorectal cancer. Nat Commun. 13:39712022.
View Article : Google Scholar : PubMed/NCBI
|
|
89
|
Gan SS, Ye JQ, Wang L, Qu FJ, Chu CM, Tian
YJ, Yang W and Cui XG: Inhibition of PCSK9 protects against
radiationinduced damage of prostate cancer cells. Onco Targets
Ther. 10:2139–2146. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
90
|
Kuang H, Lyu JH and Li T: Cholesterol
metabolism and tumor radiotherapy. J Nutr Oncol. 8:121–128. 2023.
View Article : Google Scholar
|
|
91
|
Yang J, Wang L and Jia R: Role of de novo
cholesterol synthesis enzymes in cancer. J Cancer. 11:1761–1767.
2020. View Article : Google Scholar : PubMed/NCBI
|
|
92
|
Alannan M, Trézéguet V, Amoêdo ND,
Rossignol R, Mahfouf W, Rezvani HR, Dittrich-Domergue F, Moreau P,
Lacomme S, Gontier E, et al: Rewiring lipid metabolism by targeting
PCSK9 and HMGCR to treat liver cancer. Cancers (Basel). 15:32022.
View Article : Google Scholar : PubMed/NCBI
|
|
93
|
Benador IY, Veliova M, Liesa M and
Shirihai OS: Mitochondria bound to lipid droplets: Where
mitochondrial dynamics regulate lipid storage and utilization. Cell
Metab. 29:827–835. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
94
|
Alannan M, Fatrouni H, Trézéguet V,
Dittrich-Domergue F, Moreau P, Siegfried G, Liet B, Khatib AM,
Grosset CF, Badran B, et al: Targeting PCSK9 in liver cancer cells
triggers metabolic exhaustion and cell death by ferroptosis. Cells.
12:622022. View Article : Google Scholar : PubMed/NCBI
|
|
95
|
Schmidt AF, Swerdlow DI, Holmes MV, Patel
RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hyppönen E,
Power C, et al: PCSK9 genetic variants and risk of type 2 diabetes:
A mendelian randomisation study. Lancet Diabetes Endocrinol.
5:97–105. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
96
|
Marku A, Da Dalt L, Galli A, Dule N,
Corsetto P, Rizzo AM, Moregola A, Uboldi P, Bonacina F, Marciani P,
et al: Pancreatic PCSK9 controls the organization of the β-cell
secretory pathway via LDLR-cholesterol axis. Metabolism.
136:1552912022. View Article : Google Scholar : PubMed/NCBI
|
|
97
|
Liu Z, Chen H, Zheng L, Sun L and Shi L:
Angiogenic signaling pathways and anti-angiogenic therapy for
cancer. Signal Transduct Target Ther. 8:1982023. View Article : Google Scholar : PubMed/NCBI
|
|
98
|
Feleszko W, Bałkowiec EZ, Sieberth E,
Marczak M, Dabrowska A, Giermasz A, Czajka A and Jakóbisiak M:
Lovastatin and tumor necrosis factor-α exhibit potentiated
antitumor effects against Ha-ras-transformed murine tumor Via
inhibition of tumor-induced angiogenesis. Int J Cancer. 81:560–567.
1999. View Article : Google Scholar : PubMed/NCBI
|
|
99
|
Zhan X, Jiang L, Wang L, Liu J, Kang S,
Liu H and Lin L: A novel angiogenic effect of PCSK9-regulated
genes. Gene. 852:1470512023. View Article : Google Scholar : PubMed/NCBI
|
|
100
|
Safaeian L, Vaseghi G, Jabari H and Dana
N: Evolocumab, a proprotein convertase subtilisin/kexin type 9
inhibitor, promotes angiogenesis in vitro. Can J Physiol Pharmacol.
97:352–358. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
101
|
Rada M, Reynolds AR, Lazaris A, Seidah N
and Metrakos P: Inhibition of proprotein convertase subtilisin-like
kexin type 9 (PCSK9) potentiates anti-angiogenic therapy in
colorectal cancer liver metastases. bioRxiv. May 29–2023.doi:
10.1101/2023.05.29.542731.
|
|
102
|
Tufail M, Jiang CH and Li N: Immune
evasion in cancer: Mechanisms and cutting-edge therapeutic
approaches. Signal Transduct Target Ther. 10:2272025. View Article : Google Scholar : PubMed/NCBI
|
|
103
|
Lagunas-Rangel FA: Cholesterol effects on
the tumor immune microenvironment: From fundamental concepts to
mechanisms and implications. Front Oncol. 15:15790542025.
View Article : Google Scholar : PubMed/NCBI
|
|
104
|
Bai W: The combined characteristics of
cholesterol metabolism and the immune microenvironment may serve as
valuable biomarkers for both the prognosis and treatment of
hepatocellular carcinoma. Heliyon. 9:e228852023. View Article : Google Scholar : PubMed/NCBI
|
|
105
|
Chen Y, Xu Y, Zhao H, Zhou Y, Zhang J, Lei
J, Wu L, Zhou M, Wang J, Yang S, et al: Myeloid-derived suppressor
cells deficient in cholesterol biosynthesis promote tumor immune
evasion. Cancer Lett. 564:2162082023. View Article : Google Scholar : PubMed/NCBI
|
|
106
|
Yuan J, Cai T, Zheng X, Ren Y, Qi J, Lu X,
Chen H, Lin H, Chen Z, Liu M, et al: Potentiating CD8+ T cell
antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR
recycling and signaling. Protein Cell. 12:240–260. 2021. View Article : Google Scholar : PubMed/NCBI
|
|
107
|
Peng Z, Lv SJ, Chen H, Guo Z, Wan Q, Yang
J, Zhang Y, Liu DP, Chen HZ and Wang M: Disruption of PCSK9
suppresses inflammation and attenuates abdominal aortic aneurysm
formation. Arterioscler Thromb Vasc Biol. 45:e1–e14. 2025.
View Article : Google Scholar : PubMed/NCBI
|
|
108
|
Macchi C, Greco MF, Botta M, Sperandeo P,
Dongiovanni P, Valenti L, Cicero AFG, Borghi C, Lupo MG, Romeo S,
et al: Leptin, resistin, and proprotein convertase Subtilisin/Kexin
Type 9: The role of STAT3. Am J Pathol. 190:2226–2236. 2020.
View Article : Google Scholar : PubMed/NCBI
|
|
109
|
Wang Y, Fang X, Liu J, Lv X, Lu K, Lu Y
and Jiang Y: PCSK9 in T-cell function and the immune response.
Biomark Res. 12:1632024. View Article : Google Scholar : PubMed/NCBI
|
|
110
|
Tang Z, Jiang L, Peng J, Ren Z, Wei D, Wu
C, Pan L, Jiang Z and Liu L: PCSK9 siRNA suppresses the
inflammatory response induced by oxLDL through inhibition of NF-κB
activation in THP-1-derived macrophages. Int J Mol Med. 30:931–938.
2012. View Article : Google Scholar : PubMed/NCBI
|
|
111
|
Ricci C, Ruscica M, Camera M, Rossetti L,
Macchi C, Colciago A, Zanotti I, Lupo MG, Adorni MP, Cicero AFG, et
al: PCSK9 induces a pro-inflammatory response in macrophages. Sci
Rep. 8:22672018. View Article : Google Scholar : PubMed/NCBI
|
|
112
|
Wang F, Li M, Zhang A, Li H, Jiang C and
Guo J: PCSK9 modulates macrophage polarization-mediated ventricular
remodeling after myocardial infarction. J Immunol Res.
2022:76857962022. View Article : Google Scholar : PubMed/NCBI
|
|
113
|
Jaén RI, Povo-Retana A, Rosales-Mendoza C,
Capillas-Herrero P, Sánchez-García S, Martín-Sanz P, Mojena M,
Prieto P and Boscá L: Functional crosstalk between PCSK9
internalization and Pro-inflammatory activation in human
macrophages: Role of reactive oxygen species release. Int J Mol
Sci. 23:91142022. View Article : Google Scholar : PubMed/NCBI
|
|
114
|
Katsuki S, Jha PK, Lupieri A, Nakano T,
Passos LSA, Rogers MA, Becker-Greene D, Le TD, Decano JL, Ho Lee L,
et al: Proprotein convertase Subtilisin/Kexin 9 (PCSK9) promotes
macrophage activation via LDL Receptor-independent mechanisms. Circ
Res. 131:873–889. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
115
|
Liu A and Frostegård J: PCSK9 plays a
novel immunological role in oxidized LDL-induced dendritic cell
maturation and activation of T cells from human blood and
atherosclerotic plaque. J Intern Med. 284:193–210. 2018. View Article : Google Scholar
|
|
116
|
Meng Y, Zheng X, Zhang Z, Geng H and Li X:
Circulating PCSK9 relates to aggravated disease activity, Th17/Treg
imbalance, and predicts treatment outcome of conventional synthetic
DMARDs in rheumatoid arthritis patients. Ir J Med Sci.
192:3187–3194. 2023. View Article : Google Scholar : PubMed/NCBI
|
|
117
|
Lao M, Zhang X, Li Z, Sun K, Yang H, Wang
S, He L, Chen Y, Zhang H, Shi J, et al: Lipid metabolism
reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer
to immunochemotherapy. Cancer Commun. 45:1010–1037. 2025.
View Article : Google Scholar : PubMed/NCBI
|
|
118
|
Gao X, Yi L, Jiang C, Li S, Wang X, Yang
B, Li W, Che N, Wang J, Zhang H and Zhang S: PCSK9 regulates the
efficacy of immune checkpoint therapy in lung cancer. Front
Immunol. 14:11424282023. View Article : Google Scholar : PubMed/NCBI
|
|
119
|
Wang R, Liu H, He P, An D, Guo X, Zhang X
and Feng M: Inhibition of PCSK9 enhances the antitumor effect of
PD-1 inhibitor in colorectal cancer by promoting the infiltration
of CD8+ T cells and the exclusion of Treg cells. Front Immunol.
13:9477562022. View Article : Google Scholar : PubMed/NCBI
|
|
120
|
Gu Y, Lin X, Dong Y, Wood G, Seidah NG,
Werstuck G, Major P, Bonert M, Kapoor A and Tang D: PCSK9
facilitates melanoma pathogenesis via a network regulating tumor
immunity. J Exp Clin Cancer Res. 42:22023. View Article : Google Scholar : PubMed/NCBI
|
|
121
|
Yang QC, Wang S, Liu YT, Song A, Wu ZZ,
Wan SC, Li HM and Sun ZJ: Targeting PCSK9 reduces cancer cell
stemness and enhances antitumor immunity in head and neck cancer.
iScience. 26:1069162023. View Article : Google Scholar : PubMed/NCBI
|
|
122
|
Ioannou GN, Lee SP, Linsley PS, Gersuk V,
Yeh MM, Chen YY, Peng YJ, Dutta M, Mascarinas G, Molla B, et al:
Pcsk9 deletion promotes murine nonalcoholic steatohepatitis and
hepatic carcinogenesis: Role of cholesterol. Hepatol Commun.
6:780–794. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
123
|
Hu J, Zhang M, Gui L, Wan Q, Zhong J, Bai
L and He M: PCSK9 suppresses M2-Like Tumor-associated macrophage
polarization by regulating the secretion of OX40L from
Hepatocellular carcinoma cells. Immunol Invest. 51:1678–1693. 2022.
View Article : Google Scholar : PubMed/NCBI
|
|
124
|
Chong ÉW, Joncas FH, Seidah NG, Calon F,
Diorio C and Gangloff A: Circulating Levels of PCSK9, ANGPTL3 and
Lp(a) in stage III breast cancers. J Clin Lipidol. 16:e3–e4. 2022.
View Article : Google Scholar
|
|
125
|
Bonaventura A, Grossi F, Carbone F,
Vecchié A, Minetti S, Bardi N, Elia E, Ansaldo AM, Ferrara D,
Rijavec E, et al: Serum PCSK9 levels at the second nivolumab cycle
predict overall survival in elderly patients with NSCLC: A pilot
study. Cancer Immunol Immunother. 68:1351–1358. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
126
|
Xie M, Yu X, Chu X, Xie H, Zhou J, Zhao J
and Su C: Low baseline plasma PCSK9 level is associated with good
clinical outcomes of immune checkpoint inhibitors in advanced
non-small cell lung cancer. Thorac Cancer. 13:353–360. 2022.
View Article : Google Scholar : PubMed/NCBI
|
|
127
|
Baass A, Dubuc G, Tremblay M, Delvin EE,
O'Loughlin J, Levy E, Davignon J and Lambert M: Plasma PCSK9 is
associated with age, sex, and multiple metabolic markers in a
population-based sample of children and adolescents. Clin Chem.
55:1637–1645. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
128
|
Zhang N, Gu T, Hu S, Liu T and Chen K:
PCSK9 inhibitor with cause-specific mortality amongst cancer
survivors : A chance to kill two birds with one stone. Eur J Prev
Cardiol. 33:612–614. 2026. View Article : Google Scholar : PubMed/NCBI
|
|
129
|
Wang W, Li W, Zhang D, Mi Y, Zhang J and
He G: The causal relationship between PCSK9 inhibitors and
malignant tumors: A mendelian randomization study based on drug
targeting. Genes (Basel). 15:1322024. View Article : Google Scholar : PubMed/NCBI
|
|
130
|
Wong Chong E, Joncas FH, Seidah NG, Calon
F, Diorio C and Gangloff A: Circulating levels of PCSK9, ANGPTL3
and Lp(a) in stage III breast cancers. BMC Cancer. 22:10492022.
View Article : Google Scholar : PubMed/NCBI
|
|
131
|
Wu Z, Wu D, Huang C, Zhang J, Sun S, Chen
Y, Sun Y and Ma M: Prognostic implications of PCSK9 expression in
HER2-positive breast cancer. Oncologie. 27:295–305. 2025.
View Article : Google Scholar
|
|
132
|
Sun C, Zhu G, Shen C, Huang S, Li R, Li J,
Ma Z and Wang Z: Identification and validation of PCSK9 as a
prognostic and immune-related influencing factor in tumorigenesis:
A pan-cancer analysis. Front Oncol. 13:11340632023. View Article : Google Scholar : PubMed/NCBI
|
|
133
|
Ito M, Hiwasa T, Oshima Y, Yajima S,
Suzuki T, Nanami T, Sumazaki M, Shiratori F, Funahashi K, Li SY, et
al: Association of serum Anti-PCSK9 antibody levels with favorable
postoperative prognosis in esophageal cancer. Front Oncol.
11:7080392021. View Article : Google Scholar : PubMed/NCBI
|
|
134
|
Wood C, Lyniv L, Isaacs JM, Kaufman JM,
Oduah EI, Clarke J, Crawford J, Stinchcombe T, Tong BC, Wang X, et
al: Perioperative pembrolizumab in early-stage non-small cell lung
cancer (NSCLC): Safety, efficacy, and exploratory biomarker
analysis. J Immunother Cancer. 13:e0103952025. View Article : Google Scholar : PubMed/NCBI
|
|
135
|
Walley KR, Thain KR, Russell JA, Reilly
MP, Meyer NJ, Ferguson JF, Christie JD, Nakada TA, Fjell CD, Thair
SA, et al: PCSK9 is a critical regulator of the innate immune
response and septic shock outcome. Sci Transl Med. 6:258ra1432014.
View Article : Google Scholar : PubMed/NCBI
|
|
136
|
Picard C, Poirier A, Bélanger S, Labonté
A, Auld D and Poirier J: Proprotein convertase subtilisin/kexin
type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic
multi-cohort study. PLoS One. 14:e02202542019. View Article : Google Scholar : PubMed/NCBI
|
|
137
|
Hanahan D: Hallmarks of cancer: New
dimensions. Cancer Discov. 12:31–46. 2022. View Article : Google Scholar : PubMed/NCBI
|
|
138
|
Wang L, Wang C, Sarwar MS, Chou P, Wang Y,
Su X and Kong ANT: PTEN-knockout regulates metabolic rewiring and
epigenetic reprogramming in prostate cancer and chemoprevention by
triterpenoid ursolic acid. FASEB J. 36:e226262022. View Article : Google Scholar : PubMed/NCBI
|
|
139
|
Howe C, Mitchell J, Kim SJ, Im E and Rhee
SH: Pten gene deletion in intestinal epithelial cells enhances
susceptibility to Salmonella Typhimurium infection in mice. J
Microbiol. 57:1012–1018. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
140
|
Xiao M, Xu J, Wang W, Zhang B, Liu J, Li
J, Xu H, Zhao Y, Yu X and Shi S: Functional significance of
cholesterol metabolism in cancer: From threat to treatment. Exp Mol
Med. 55:1982–1995. 2023. View Article : Google Scholar : PubMed/NCBI
|
|
141
|
Moşteoru S, Gaiţă D and Banach M: An
update on PCSK9 inhibitors-pharmacokinetics, drug interactions, and
toxicity. Expert Opin Drug Metab Toxicol. 16:1199–1205. 2020.
View Article : Google Scholar : PubMed/NCBI
|
|
142
|
Farnier M, Hovingh GK, Langslet G, Dufour
R, Baccara-Dinet MT, Din-Bell C, Manvelian G and Guyton JR:
Long-term safety and efficacy of alirocumab in patients with
heterozygous familial hypercholesterolemia: An open-label extension
of the ODYSSEY program. Atherosclerosis. 278:307–314. 2018.
View Article : Google Scholar : PubMed/NCBI
|
|
143
|
Hori M, Ohta N, Takahashi A, Masuda H,
Isoda R, Yamamoto S, Son C, Ogura M, Hosoda K, Miyamoto Y and
Harada-Shiba M: Impact of LDLR and PCSK9 pathogenic variants in
Japanese heterozygous familial hypercholesterolemia patients.
Atherosclerosis. 289:101–108. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
144
|
Abifadel M, Guerin M, Benjannet S, Rabès
JP, Le Goff W, Julia Z, Hamelin J, Carreau V, Varret M, Bruckert E,
et al: Identification and characterization of new gain-of-function
mutations in the PCSK9 gene responsible for autosomal dominant
hypercholesterolemia. Atherosclerosis. 223:394–400. 2012.
View Article : Google Scholar : PubMed/NCBI
|
|
145
|
Raal FJ, Bahassi EM, Stevens B, Turner TA
and Stein EA: Cascade screening for familial hypercholesterolemia
in south africa: The Wits FIND-FH program. Arterioscler Thromb Vasc
Biol. 40:2747–2755. 2020. View Article : Google Scholar : PubMed/NCBI
|
|
146
|
Burke AC, Dron JS, Hegele RA and Huff MW:
PCSK9: Regulation and target for drug development for dyslipidemia.
Annu Rev Pharmacol Toxicol. 57:223–244. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
147
|
Medeiros AM, Alves AC and Bourbon M:
Mutational analysis of a cohort with clinical diagnosis of familial
hypercholesterolemia: Considerations for genetic diagnosis
improvement. Genet Med. 18:316–324. 2016. View Article : Google Scholar : PubMed/NCBI
|
|
148
|
Xiang R, Fan LL, Lin MJ, Li JJ, Shi XY,
Jin JY, Liu YX, Chen YQ, Xia K and Zhao SP: The genetic spectrum of
familial hypercholesterolemia in the central south region of China.
Atherosclerosis. 258:84–88. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
149
|
Grejtakova D, Boronova I, Bernasovska J
and Bellosta S: PCSK9 and lipid metabolism: Genetic variants,
current therapies, and cardiovascular outcomes. Cardiovasc Drugs
Ther. 39:1439–1451. 2025. View Article : Google Scholar : PubMed/NCBI
|
|
150
|
Maligłówka M, Kosowski M, Hachuła M,
Cyrnek M, Bułdak Ł, Basiak M, Bołdys A, Machnik G, Bułdak RJ and
Okopień B: Insight into the Evolving role of PCSK9. Metabolites.
12:2562022. View Article : Google Scholar : PubMed/NCBI
|
|
151
|
Garvie CW, Fraley CV, Elowe NH, Culyba EK,
Lemke CT, Hubbard BK, Kaushik VK and Daniels DS: Point mutations at
the catalytic site of PCSK9 inhibit folding, autoprocessing, and
interaction with the LDL receptor. Protein Sci. 25:2018–2027. 2016.
View Article : Google Scholar : PubMed/NCBI
|
|
152
|
Ahmed W, Whittall R, Riaz M, Ajmal M,
Sadeque A, Ayub H, Qamar R and Humphries SE: The genetic spectrum
of familial hypercholesterolemia in Pakistan. Clin Chim Acta.
421:219–225. 2013. View Article : Google Scholar : PubMed/NCBI
|
|
153
|
Larrea-Sebal A, Trenti C,
Jebari-Benslaiman S, Bertolini S, Calandra S, Negri EA, Bonelli E,
Benito-Vicente A, Uraga-Gracianteparaluceta L, Martín C and Fasano
T: Functional characterization of p.(Arg160Gln) PCSK9 variant
accidentally found in a hypercholesterolemic subject. Int J Mol
Sci. 24:33302023. View Article : Google Scholar : PubMed/NCBI
|
|
154
|
Homer VM, Marais AD, Charlton F, Laurie
AD, Hurndell N, Scott R, Mangili F, Sullivan DR, Barter PJ, Rye KA,
et al: Identification and characterization of two non-secreted
PCSK9 mutants associated with familial hypercholesterolemia in
cohorts from New Zealand and South Africa. Atherosclerosis.
196:659–666. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
155
|
Uribe KB, Chemello K, Larrea-Sebal A,
Benito-Vicente A, Galicia-Garcia U, Bourane S, Jaafar AK, Lambert G
and Martín C: A systematic approach to assess the activity and
classification of pcsk9 variants. Int J Mol Sci. 22:136022021.
View Article : Google Scholar : PubMed/NCBI
|
|
156
|
Cao YX, Wu NQ, Sun D, Liu HH, Jin JL, Li
S, Guo YL, Zhu CG, Gao Y, Dong QT, et al: Application of expanded
genetic analysis in the diagnosis of familial hypercholesterolemia
in patients with very early-onset coronary artery disease. J Transl
Med. 16:3452018. View Article : Google Scholar : PubMed/NCBI
|
|
157
|
Abul-Husn NS, Manickam K, Jones LK, Wright
EA, Hartzel DN, Gonzaga-Jauregui C, O'Dushlaine C, Leader JB,
Lester Kirchner H, Lindbuchler DM, et al: Genetic identification of
familial hypercholesterolemia within a single U.S. Health care
system. Science. 354:aaf70002016. View Article : Google Scholar : PubMed/NCBI
|
|
158
|
Hyock JK, Lagace TA, McNutt MC, Horton JD
and Deisenhofer J: Molecular basis for LDL receptor recognition by
PCSK9. Proc Natl Acad Sci USA. 105:1820–1825. 2008. View Article : Google Scholar
|
|
159
|
Tosi I, Toledo-Leiva P, Neuwirth C,
Naoumova RP and Soutar AK: Genetic defects causing familial
hypercholesterolaemia: Identification of deletions and duplications
in the LDL-receptor gene and summary of all mutations found in
patients attending the Hammersmith Hospital Lipid Clinic.
Atherosclerosis. 194:102–111. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
160
|
Kim HN, Kweon SS and Shin MH: Detection of
familial hypercholesterolemia using next generation sequencing in
two Population-based cohorts. Chonnam Med J. 54:312018. View Article : Google Scholar : PubMed/NCBI
|
|
161
|
Sánchez-Hernández RM, Tugores A, Nóvoa FJ,
Brito-Casillas Y, Expósito-Montesdeoca AB, Garay P, Bea AM, Riaño
M, Pocovi M, Civeira F, et al: The island of Gran Canaria: A
genetic isolate for familial hypercholesterolemia. J Clin Lipidol.
13:618–626. 2019. View Article : Google Scholar : PubMed/NCBI
|
|
162
|
Wang J, Dron JS, Ban MR, Robinson JF,
McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, et
al: Polygenic versus monogenic causes of hypercholesterolemia
ascertained clinically. Arterioscler Thromb Vasc Biol.
36:2439–2445. 2016. View Article : Google Scholar : PubMed/NCBI
|
|
163
|
Lee C, Cui Y, Song J, Li S, Zhang F, Wu M,
Li L, Hu D and Chen H: Effects of familial
hypercholesterolemia-associated genes on the phenotype of premature
myocardial infarction. Lipids Health Dis. 18:952019. View Article : Google Scholar : PubMed/NCBI
|
|
164
|
Lee CJ, Lee Y, Park S, Kang SM, Jang Y,
Lee JH and Lee SH: Rare and common variants of APOB and PCSK9 in
Korean patients with extremely low low-density
lipoprotein-cholesterol levels. PLoS One. 12:e01864462017.
View Article : Google Scholar : PubMed/NCBI
|
