Introduction
MicroRNAs (miRNAs/miRs) are concise, endogenous
non-coding RNAs, typically ~22 nucleotides in length, which serve a
crucial role in the orchestration of gene expression within
multicellular organisms, exerting influence over mRNA stability and
translation (1). The dysregulation
of miRNAs is frequently implicated in the malignant transformation
of cells, as highlighted in previous research (2). miRNAs contribute significantly to
biological processes underpinning cancer progression, metastasis,
and the development of resistance to treatment (3).
One such miRNA of interest is miR-325, which resides
in the first sub-band of region 2 on the short arm of the X
chromosome (1). miR-325 has
garnered attention due to its aberrant expression across >10
types of cancer. Given its location on the sex chromosomes, there
is a hypothesis that the regulation of miR-325 expression may be
linked to sex differences. However, prior investigations have often
overlooked sex differences in the selection of cell lines,
prompting the need for more comprehensive exploration in this area
(2,4).
Further analysis of miR-325 regulation has unveiled
its interaction with six competing endogenous RNAs (ceRNAs),
comprising one circular RNA (circRNA), four long non-coding RNAs
(lncRNAs) and one additional miRNA. miR-325 exerts its regulatory
influence by targeting and inhibiting 20 protein-coding genes
(PCGs), thereby modulating key cancer cell behaviors, including the
cell cycle, proliferation, epithelial-mesenchymal transition (EMT),
apoptosis, invasion and migration (5–7). The
present review also revealed a notable association between
diminished expression of miR-325 and shortened overall survival
(OS) and progression-free survival (PFS) across various types of
cancer. Furthermore, miR-325 has been implicated in resistance to
three anticancer drugs, and may actively participate in the
molecular mechanisms of action associated with oxaliplatin
(8), cisplatin (CDDP) (9,10) and
doxorubicin (DOX) (11).
The aim of this review was to systematically examine
the current state of research surrounding miR-325, including its
abnormal expression, molecular mechanisms and clinical
implications. By providing a consolidated overview of the knowledge
on miR-325, this review seeks to offer valuable insights to guide
future investigations in this field.
Abnormal expression of miR-325 in
cancer
As illustrated in Table
I, miR-325 exhibits consistent downregulation in both cellular
and tissue contexts across eight distinct cancer types. Notably,
miR-325 is downregulated in colorectal cancer (CRC) (4,5,11),
gastric cancer (GC) (12,13), HCC (8,14,15),
bladder urothelial carcinoma (BLCA) (6,16,17),
non-small cell lung cancer (NSCLC) (18,19),
oral squamous cell carcinoma (OSCC) (20) and papillary thyroid cancer (PTC)
(21). In addition, miR-325
expression is downregulated in a T-cell acute lymphoblastic
leukemia (T-ALL) cell line (5).
Notably, miR-325 demonstrates heightened expression levels in
glioblastoma multiforme and lower-grade glioma (GBM/LGG) (22) and nasopharyngeal carcinoma (NPC)
(23). Meanwhile, the status of
miR-325 expression in breast cancer (BC) (23,24)
appears to be contentious.
 | Table I.Aberrant expression of miR-325 in
various types of cancer. |
Table I.
Aberrant expression of miR-325 in
various types of cancer.
| A, Digestive
system |
|---|
|
|---|
| First author,
year | Cancer | miR-325
expression | Cell line | Tissue or
serum | (Refs.) |
|---|
| Zhang, 2021 | CRC | Downregulated | FHC versus HT29 and
SW480 | Paracancerous
tissues versus CRC tissues from patients | (8) |
| He, 2021 | CRC | Downregulated | NCM460 versus HT29,
SW620, HCT116 and SW480 | Paracancerous
tissues versus CRC tissues from patients | (5) |
| Li, 2021 | CRC | Downregulated | CT-26 versus CD115
and RANK | NA | (13) |
| Huang, 2023 | GC | Downregulated | HGC-27c versus
SGC-7901 | NA | (14) |
| Sun, 2020 | GC | Downregulated | NA | Adjacent normal
gastric epithelium tissues versus GC tissues from the 137
patients | (9) |
| Li, 2021 | HCC | Downregulated | NA | 20 pairs of
paracancerous tissues versus HCC tissues from patients | (15) |
| Zhang, 2019 | HCC | Downregulated | HepG2 and Huh7
versus HepG2.2.15 and Huh70-1.3 | 20 pairs of
paracancerous tissues versus HBV-HCC tissues from patients | (16) |
| Li, 2015 | HCC | Downregulated | LO2 versus
SMMC-7721, Hep3B, HepG2, Huh7 and Bel7404 | Paracancerous
tissues versus HCC tissue from the 99 patients | (12) |
|
| B, Urinary
system |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| Lin, 2018 | BLCA | Downregulated | HT-1197 and HS228
versus T24, RT4, 5637, HT-1376, J82, UM-UC-3 and TCCSUP | Paracancerous
tissues versus BLCA tissues from 164 patients | (17) |
| Sun, 2020 | BLCA | Downregulated | T24, J82 and UMUC3
versus SV-HUC-1, SW780 and HT1376 | Paracancerous
tissues versus BLCA tissues from 30 patients | (6) |
| Li, 2020 | BLCA | Downregulated | T24 and 5637 versus
5637-R and T24-R cells | NA | (18) |
|
| C, Nervous
system |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| Xiong, 2021 | GBM/LGG | Upregulated | NHA, SW1783 versus
U87 and LN229 | Paracancerous
tissues versus BLCA tissues from 24 patients | (22) |
|
| D, Respiratory
system |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| Gan, 2019 | NSCLC | Downregulated | NA | Paracancerous
tissues versus NSCLC tissues from patients | (7) |
| Yao, 2015 | NSCLC | Downregulated | 16HBE versus A549,
H358, H1299, H1650 and SPCA1 | 107 pairs of
paracancerous tissues versus NSCLC tissues from patients | (19) |
| Liu, 2021 | NPC | Upregulated | NP69 versus 5-8F,
C666-1, SUNE1 and 6-10B | Paracancerous
tissues versus NPC tissues from patients | (23) |
|
| E,
Derma |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| Chen, 2022 | OSCC | Downregulated | NA | Paracancerous
tissues versus OSCC tissues from patients | (20) |
|
| F, Circulatory
system |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| He, 2021 | T-ALL | Downregulated | T cell versus
Jurkat, CCRF-CEM, TALL-1 and KOPTK1 | Paracancerous
tissues versus T-ALL tissues from patients | (5) |
|
| G, Reproductive
system |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| Wang, 2021 | BC | Upregulated | MCF10A versus
MDA-MB-231, MDA-MB-453, MDA-MB-468, BT-20 and MCF7 | Noncancerous
tissues versus primary BC tissues from 30 patients | (24) |
| Liu, 2023 | BC | Downregulated | MB157 versus
MDA-MB-231, MDA-MB-436, SK-BR-3 and CAMA-1 | Paracancerous
tissues versus BC tissue from 15 patients | (29) |
|
| H, Endocrine
system |
|
| First author,
year | Cancer | miR-325
expression | Cell
line | Tissue or
serum | (Refs.) |
|
| Xin, 2020 | PTC | Downregulated | Nthyori3-1 versus
BHP5-16, TPC1, K1 and BHP2-7 | Paracancerous
tissues versus PTC tissue from 24 patients | (21) |
As shown in Table I
and Fig. 1, a comprehensive
analysis was conducted by comparing the expression differences of
miR-325 between cancer tissues and corresponding para-cancerous
tissues, as well as between cancer cells and para-cancerous cells,
across 11 cancer types.
 | Figure 1.miR-325 and the regulation of cancer
cell behaviors. miR-325 can regulate a variety of cancer cell
biological behaviors through its competing endogenous RNA networks
or target genes. Arrows indicate enhancement and flat lines
indicate inhibition. miR, microRNA; NSCLC, non-small cell lung
cancer; CRC, colorectal cancer; BLCA, bladder urothelial carcinoma;
HCC, hepatocellular carcinoma; SKCM, skin cutaneous melanoma;
T-ALL, T-cell acute lymphoblastic leukemia; NPC, nasopharyngeal
carcinoma; BC, breast cancer; PTC, papillary thyroid cancer; GC,
gastric cancer; GBM/LGG, glioblastoma multiforme and lower-grade
glioma; EMT, epithelial-mesenchymal transition. |
miR-325 and cancer cell behaviors
As shown in Fig. 1
and Table II, miR-325 is
considered a potent regulator that can inhibit 20 PCGs, thereby
exerting control over various cancer cell behaviors, such as
proliferation, EMT, apoptosis, invasion and migration.
| Table II.Target genes of miR-325 and effects
of miR-325 by targeting PCGs in vitro and in
vivo. |
Table II.
Target genes of miR-325 and effects
of miR-325 by targeting PCGs in vitro and in
vivo.
| First author,
year | Cancer | PCG | Effect in
vitro | Cell line | Effect in
vivo | Xenograft
model | (Refs.) |
|---|
| Gan, 2019 | NSCLC | KIF2C | Migration (+),
invasion (−) and cell cycle (−) | A549, H1299, H226
and H520 | NA | NA | (7) |
| Yao, 2015 | NSCLC | HMGB1 | Proliferation (−)
and invasion (−) | A549, H1299, SPCA1,
H1650, H358 and 16HBE | NA | NA | (19) |
| Wang, 2022 | NSCLC | GPX2 | Proliferation (−),
migration (−), invasion (−), and cisplatin resistance (−) | A549 and
NCIH1385 | Tumor growth
(−) | BEAS-2B cell
xenograft in BALB/c male mice | (10) |
| Zhang, 2021 | CRC | HSPA12B | Viability (−) | HT29 and SW480 | NA | NA | (8) |
| He, 2021 | CRC | TRIM14 | Proliferation (−),
migration (−) and invasion (−) | HT29, SW620, HCT116
and SW480 | NA | NA | (5) |
| Li, 2021 | CRC | S100A4 | Osteoclasto-genesis
(−) | CT-26 | Tumor growth
(−) | CT-26 cell
xenograft in BALB/c male mice | (13) |
| Sun, 2020 | BLCA | MT3 | Proliferation (−),
migration (−), invasion (−), and EMT (−) | T24 | NA | NA | (6) |
| Han, 2013 | HCC | ACP5 | Migration (−) and
invasion (−) | HA22T | Tumor metastasis
(−) | HA22T xenograft in
nude mouse | (31) |
| Li, 2015 | HCC | HMGB1 | Proliferation (−)
and invasion (−) | LO2 versus
SMMC-7721, Hep3B, HepG2, Huh7 and Bel7404 | NA | NA | (12) |
| Li, 2021 | HCC | CXCL17 | Proliferation (−),
migration (−), invasion (−) and angiogenesis (−) | HepG2, Bel-7402 and
SMMC-7721 | NA | NA | (15) |
| Li, 2019 | HCC | DPAGT1 | Proliferation (−),
apoptosis (+) and DOX resistance (−) | Huh7-1.3 and
HepG2.2.15 | Tumor growth
(−) | Huh7e1.3 and DOX-R
xenograft in nude mice | (11) |
| Zhang, 2019 | HCC | AQP5 | Proliferation (−)
and apoptosis (+) | Huh7-1.3 and
HepG2.2.15 | NA | NA | (16) |
| Sun, 2020 | SKCM | MAP3K2 | Proliferation (−),
migration (−) and invasion (−) | A375 and
SK-MEL-1 | NA | NA | (27) |
| He, 2021 | T-ALL | BAG2 | Proliferation (−)
and apoptosis (+) | Jurkat | NA | NA | (5) |
| Liu, 2021 | NPC | CDCA5 | Proliferation (−),
migration (−) and invasion (−) | 5-8F and
C666-1 | NA | NA | (23) |
| Liu, 2023 | BC | LCN15 | Proliferation (−),
migration (−) and invasion (−) | SK-BR-3 and
CAMA-1 | NA | NA | (29) |
| Wang, 2021 | BC | S100A2 | Proliferation (+),
invasion (+) and EMT (+) | MDA-MB-231 and
MCF7 | NA | NA | (24) |
| Xin, 2020 | PTC | DDX5 | Proliferation (−)
and migration (−) | BHP5-16, TPC1, K1
and BHP2-7 | NA | NA | (21) |
| Huang, 2023 | GC | HuR | Proliferation (−)
and apoptosis (+) | SGC-7901 and
HGC-27 | Tumor growth
(−) | SGC-7901-GFP cells
xenograft in larval zebrafish | (14) |
| Sun, 2020 | GC | DPAGT1 | Proliferation (−)
and apoptosis (+) | MKN45 | NA | NA | (9) |
| Xiong, 2021 | GBM/LGG | FOXM1 | Proliferation (−),
migration (−) and invasion (−) | SW1783 and U87 | Tumor growth
(−) | U87 cell xenograft
in BALB/c nude mice | (22) |
Cell cycle orchestration involves a complex
interplay of proteins, enzymes, cytokines and signaling pathways,
which are crucial for cell proliferation and repair (25). In NSCLC, miR-325 has been shown to
impede the progression of the cell cycle S phase or G2/M
phase in the HCT116 cell line by targeting the gene kinesin family
member 2C (KIF2C) (7).
Cancer proliferation signifies a dysregulated
balance between cell gain and loss, where mutant tumor cells
proliferate faster than they die (26). miR-325 has been reported to curtail
cancer cell proliferation in NSCLC, CRC, BLCA, HCC, skin cutaneous
melanoma (SKCM), T-ALL, NPC, BC, PTC, GC and GBM/LGG by targeting
14 genes, including high mobility group box 1 (HMGB1) (8,18),
glutathione peroxidase 2 (GPX2) (10), tripartite motif containing 14
(TRIM14) (5), metallothionein 3
(MT3) (27), C-X-C motif chemokine
ligand 17 (CXCL17) (15),
dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1)
(10,12), aquaporin 5 (AQP5) (16), mitogen-activated protein kinase
kinase kinase 2 (MAP3K2) (28), BAG
cochaperone 2 (BAG2) (5), cell
division cycle associated 5 (CDCA5) (23), lipocalin 15 (LCN15) (29), DEAD-box helicase 5 (21), human antigen R(HuR) (14) and forkhead box M1 (FOXM1) (22).
Apoptosis, a well-known form of programmed cell
death, serves as a key physiological mechanism limiting cell
population expansion (26). miR-325
has been shown to enhance cancer cell apoptosis in HCC, T-ALL and
GC by targeting four genes, namely DPAGT1 (10,12),
AQP5 (16), BAG2 (5) and HuR (14).
EMT, a critical cell biological program, is
implicated in development and wound healing, and its activation is
associated with the formation of normal and cancer stem cells
(30). It has been demonstrated
that miR-325 impedes EMT progression in BLCA by targeting the gene
MT3 (27). By contrast, in BC,
miR-325 may promote EMT progression by targeting the gene S100
calcium binding protein A2 (S100A2) (24).
Cancer metastasis, the primary cause of
cancer-related death, is reliant on an increase in cell migration
during tumor progression, enabling tumor cells to escape the
primary tumor and invade adjacent tissues to form metastases
(31). miR-325 has been shown to
inhibit the invasion and migration of cancer cells in NSCLC, CRC,
BLCA, HCC, SKCM, NPC, BC and GBM/LGG by targeting 12 genes: KIF2C
(7), HMGB1 (8,18),
GPX2 (10), TRIM14 (5), MT3 (27), acid phosphatase 5 (ACP5) (32), HMGB1 (12), CXCL17 (15), MAP3K2 (28), CDCA5 (23), LCN15 (29), and FOXM1 (22). By contrast, miR-325 can promote the
invasion and migration of BC cancer cells by targeting the gene
S100A2 (24).
miR-325 and its ceRNAs
ceRNAs competitively bind to miRNA, thereby
attenuating its inhibitory influence on target mRNA and regulating
cellular activity at the post-transcriptional level (31). The ceRNA regulatory network of
miR-325, as shown in Table III
and Fig. 2, involves circRNAs and
lncRNAs serving pivotal roles in cellular biology.
 | Figure 2.ceRNA networks associated with
miR-325. This intricate network serves a pivotal role in the
regulation of diverse biological processes within cancer cells.
Notably, it exerts influence over essential cellular behaviors,
including migration, invasion, cell cycle progression,
proliferation, osteoclastogenesis, EMT, angiogenesis and apoptosis.
Across a spectrum of 11 different cancer types, the impact of the
miR-325 ceRNA networks underscores their significance in
orchestrating intricate molecular mechanisms that contribute to
cancer pathogenesis. ceRNA, competing endogenous RNA; miR,
microRNA; NSCLC, non-small cell lung cancer; CRC, colorectal
cancer; BLCA, bladder urothelial carcinoma; HCC, hepatocellular
carcinoma; SKCM, skin cutaneous melanoma; T-ALL, T-cell acute
lymphoblastic leukemia; NPC, nasopharyngeal carcinoma; BC, breast
cancer; PTC, papillary thyroid cancer; GC, gastric cancer; GBM/LGG,
glioblastoma multiforme and lower-grade glioma; EMT,
epithelial-mesenchymal transition. |
| Table III.ceRNAs of miR-325. |
Table III.
ceRNAs of miR-325.
|
|
|
| Binding site of
ceRNA and miR-325 | Binding site of
miR-325 and PCG |
|
|---|
|
|
|
|
|
|
|
|---|
| First author,
year | CeRNA axis | Cancer | ceRNA, 5′-3′ | miR-325, 3′-5′ | PCG, 5′-3′ | miRNA, 3′-5′ | (Refs.) |
|---|
| Han, 2013 |
AR/miR-325/ACP5 | HCC | NA | NA | UCAAUAA | AGUUAUU | (31) |
| Chen, 2022 |
Circ_0069313/miR-325/FOXP3 | OSCC | CAAUAAA | GUUAUUU | CAAUAAA | GUUAUUU | (20) |
| Sun, 2020 |
FOXD3-AS1/miR-325/MAP3K2 | SKCM | CUACUAG | GAUGAUC | CUACUAG | GAUGAUC | (27) |
| Liu, 2021 |
LINC01515/miR-325/CDCA5 | NPC |
AaUUgCUaGGAguugaAaCUACUAG | UgAAuGA-CCU-
UgGAUGAUC | AgACCUACUAG | UgUGGAUGAUC | (23) |
| He, 2021 |
MSC-AS1/miR-325/TRIM14 | CRC |
AgUUAuUGGuaAuaCUACUAGU |
UgAAUgACCugUgGAUGAUC | CUACUAG | GAUGAUC | (5) |
| Zhang, 2019 | miR-325/AQP5 | HCC | NA | NA | CAAUAAA | GUUAUU | (16) |
| He, 2021 | miR-325/BAG2 | T-ALL | NA | NA | UACUAG | AUGAUC | (5) |
| Li, 2021 | miR-325/CXCL17 | HCC | NA | NA | UCAAUAAA | AGUUAUUU | (15) |
| Xiong, 2021 | miR-325/FOXM1 | GBM/LGG | NA | NA | CUCAAUAA | GAGUUAUU | (22) |
| Wang, 2022 | miR-325/GPX2 | NSCLC | NA | NA | CAAUAAA | GUUAUUU | (10) |
| Yao, 2015 | miR-325/HMGB1 | NSCLC | NA | NA | GUUAUAU | CAAUAUA | (19) |
| Zhang, 2021 |
miR-325/HSPA12B | CRC | NA | NA |
GAGGUga-CAAUAAAA | CUCCAgga
GUUAUUU | (8) |
| Huang 2023 | miR-325/HuR | GC | NA | NA |
UCAAUAAA-CAAUAAA |
AGUUAUUU-GUUAUUU | (14) |
| Gan, 2019 | miR-325/KIF2C | NSCLC | NA | NA | CAAUAAA | GUUAUUU | (7) |
| Liu, 2023 | miR-325/LNC15 | BC | NA | NA | UCAAUAA | AGUUAUU | (29) |
| Sun, 2020 | miR-325/MT3 | BLCA | NA | NA | GGAGGaauga
CAAUAA | CCUCCagaa
GUUAUU | (6) |
| Wang, 2021 | miR-325/S100A2 | BC | NA | NA | AGUUAUUU | UCAAUAAA | (24) |
| Li, 2021 | miR-325/S100A4 | CRC | NA | NA | AGUUAUUU | UCAAUAAA | (13) |
circRNAs exert diverse biological functions by
serving as transcriptional regulators, miRNA sponges and protein
templates (33). As depicted in
Table III, the inhibitory impact
of miR-325 on target genes was competitively counteracted by
Circ_0069313. In OSCC, the Circ_0069313/miR-325/FOXP3 axis was
implicated in inducing OSCC cell immune escape (20).
lncRNAs are RNA molecules exceeding 200 nucleotides
in length, which are central to cellular regulation (34). The regulatory interplay involving
four lncRNAs, AR, FOXD3-AS1, LINC01515 and MSC-AS1, has been shown
to competitively inhibit miR-325 (11,22,26,30)
(Table III; Fig. 2).
The lncRNA/miR-325/PCG axis has emerged as a potent
regulator hindering cancer progression, including its inhibitory
role in HCC. Notably, the AR/miR-325/ACP5 axis has been shown to
exhibit the capability to impede invasion and migration of HCC
cells (32). Additionally, three
distinct lncRNA/miR-325/PCG axes have been implicated in promoting
cancer progression. In SKCM, the FOXD3-AS1/miR-325/MAP3K2 axis can
promote proliferation, migration and invasion of cancer cells
(28). In NPC, the
LINC01515/miR-325/CDCA5 axis has been shown to foster
proliferation, migration and invasion, while inhibiting apoptosis
(23). Similarly, in CRC, the
MSC-AS1/miR-325/TRIM14 axis may stimulate proliferation, invasion
and migration of cancer cells (5).
The base sequence of miR-325 is
3′-UGUGAAUGACCUGUGGAUGAUCC-5′ (5)
(Fig. 3A and C). Four target genes
have been observed to bind to this sequence. Specifically, miR-325
forms a binding interaction with CDCA5 through the
3′-UgUGGAUGAUC-5′ sequence (23),
TRIM14 and MAP3K2 through the 3′-GAUGAUC-5′ sequence (11,26),
and BAG2 through the 3′-AUGAUC-5′ sequence (5) (Fig.
3A). In addition, three lncRNAs have been shown to bind to the
base sequence of miR-325. The binding interactions are as follows:
miR-325 binds to LINC01515 through the 3′-UgAAuGA-CCU-gUgGAUGAUC-5′
sequence (23), MSC-AS1 through the
3′-UgAAUgACCugUgGAUGAUC-5′ sequence (5), and FOXD3-AS1 through the 3′-GAUGAUC-5′
sequence (27).
As shown in Fig. 3B,
the pre-miR-325 sequence has 13 target genes, and its base sequence
is 3′-AACUAUCCCUCCAGGAGUUAUUUGUUUAAUA-5′ (6). Pre-miR-325 forms specific binding
interactions with the following genes: MT3 through the
3′-CCUCCagaaGUUAUU-5′ sequence, heat shock protein family A member
12B (HSPA12B) through the 3′-CUCCAggaGUUAUUU-5′ sequence, ACP5 and
LCN15 through the 3′-AGUUAUU-5′ sequence, LNX1, CXCL17, S100
calcium binding protein A4 (S100A4), S100A2 and HuR through the
3′-AGUUAUUU-5′ sequence, and FOXP3, AOP5, GPX2, KIF2C and HuR
through the 3′-GUUAUUU-5′ sequence. Additionally, pre-miR-325 binds
to FOXM1 through the 3′-GAGUUAUU-5′ sequence. Furthermore, as shown
in Fig. 3D, pre-miR-325 forms a
binding interaction with Circ-0069313 through the 3′-GUUAUUU-5′
sequence.
miR-325 and cancer therapy
As illustrated in Table
IV, the prognostic significance of miR-325 is underscored by
its dysregulation, and is associated with the pathological state of
cancer tissues and diagnostic risk, influencing patient prognosis.
In GC, HCC, NSCLC and BLCA, diminished miR-325 expression has been
reported to be associated with adverse patient outcomes. In GC,
reduced miR-325 expression has been shown to align with a shorter
OS (9). Similarly, in HCC, low
miR-325 expression corresponded to earlier TNM stage, and shorter
OS and PFS, alongside factors such as tumor size and metastasis
(12). Patients with NSCLC with low
miR-325 expression exhibited shorter OS and PFS (15) (19).
In addition, in BLCA, diminished miR-325 expression was associated
with a shorter OS (17). Notably,
miR-325 has been reported to target and inhibits KIF2C expression
in NSCLC, with high KIF2C expression linked to shorter OS (7). In NPC, elevated LINC01515 expression,
suppressing miR-325, has been shown to be associated with poor
prognosis and OS in patients (23).
Similarly, in NSCLC, heightened GPX2 expression, directly targeted
by miR-325, was negatively associated with miR-325 expression, and
associated with poor prognosis and OS (10). In OSCC, hsa_circ_0069313 can bind to
miR-325, inhibiting its expression, and was thus revealed to be
associated with poor prognosis and OS (20). Furthermore, in SKCM, FOXD3-AS1,
targeted by miR-325, was upregulated and negatively associated with
miR-325 expression, contributing to poor prognosis and OS in
patients (28)
| Table IV.Prognostic value of miR-325. |
Table IV.
Prognostic value of miR-325.
| First author,
year | Cancer | Sample size | miR-325
expression | Clinicopathological
characteristics | Prognostic values
of miR-325 overexpression | (Refs.) |
|---|
| Sun, 2020 | GC | 134 | Downregulated | NA | Shorter OS | (9) |
| Li, 2015 | HCC | 99 | Downregulated | Earlier TNM stage,
larger tumor size and increased metastasis | Shorter OS and
PFS | (12) |
| Li, 2021 | NSCLC | 20 | Downregulated | NA | Shorter OS and
PFS | (15) |
| Yao, 2015 | NSCLC | 107 | Downregulated | NA | Shorter OS and
PFS | (19) |
| Lin, 2018 | BLCA | 42 | Downregulated | NA | Shorter OS | (17) |
The development of drug resistance in tumor cells
significantly contributes to the ineffectiveness of chemotherapy
(35). As shown in Fig. 4A, miR-325 may serve a crucial role
in modulating the response of cancer cells to various anticancer
drugs. Oxaliplatin is a highly effective chemotherapy agent in CRC
treatment. This third-generation platinum compound induces DNA
cross-linking in cancer cells, resulting in apoptotic cell death.
In CRC, miR-325 sensitized cancer cells to oxaliplatin-induced
cytotoxicity by modulating the HSPA12B/PI3K/AKT/Bcl-2 pathway
(8). CDDP, which is employed in
treating diverse types of human cancer, such as bladder, head and
neck, lung, ovarian and testicular cancer (36), has been shown to encounter
regulatory influence from miR-325. In GC, SNHG6 can bind to
miR-325-3p, interacting directly with GITR to regulate CDDP
resistance. GITR, in turn, promotes CDDP resistance in GC cell
lines, primarily by modulating Bcl2-mediated apoptosis (9). Notably, in NSCLC, GPX2 has been
reported to drive malignant progression and CDDP resistance in
KRAS-driven lung cancer (10). DOX
is a standard systemic chemotherapy adjuvant drug for transarterial
chemoembolization. Chemosensitivity to DOX has been reported to be
markedly increased in cells overexpressing miR-325, and the
inhibitory effects of miR-325 on chemoresistance have been shown to
be diminished upon artificially restoring DPAGT1 expression.
Meanwhile, miR-325 inhibits the expression of DPAGT1 gene in HCC.
This regulatory mechanism has been shown to phenotypically mimic
the effects of DPAGT1 silencing both in vitro and in
vivo, consequently reducing the survival rate of DOX-resistant
cells (11).
The CADDIE database (https://www.exbio.wzw.tum.de/caddie/) was used to
search potential targeted drugs of PCGs, and the obtained results
are shown in Fig. 4B. Among these,
MAP3K2 has associations with bosutinib and fostatinib, HMGB1 with
chloroquine, MT3 with zinc acetate and zinc chloride, GPX2 with
glutathione, S100A4 with trifluoperazine, and S100A2 with zinc
chloride, zinc acetate and olopatadine. Future investigations are
warranted to elucidate the potential interactions between miR-325
and these drugs.
Discussion
The findings of the present study underscore the
potential utility of miR-325 as a biomarker in various types of
cancer. In NSCLC (7), miR-325 has
emerged as a promising diagnostic and treatment target. Similarly,
in HCC (15), miR-325 may hold
promise as a biomarker for treatment. In NPC (23), LINC01515 has been shown to act as a
molecular sponge for miR-325, influencing cell division
cycle-related expression, and showcasing potential as a prognostic
biomarker or therapeutic target. In BLCA (16,26),
low-level expression of miR-325 has emerged as a biomarker for
adverse clinicopathological characteristics and poor prognosis. In
GBM/LGG (22), miR-325 was
identified as a promising prognostic biomarker.
Collectively, these findings highlight the potential
role of miR-325 as a diagnostic, therapeutic and prognostic
biomarker across different types of cancer. However, the existing
research on miR-325 has certain limitations. Notably, the
expression of miR-325 in BC appears controversial. One dataset
indicated the upregulation of miR-325 in the primary BC tissues of
30 patients compared with in non-cancerous tissues (24), whereas another dataset suggested it
was downregulated in the BC tissues of 15 patients compared with in
adjacent tissues (29).
Discrepancies in the choice of cell lines, small sample sizes and
inconsistent tumor stages among patient samples may contribute to
these variations in miR-325 expression patterns in BC.
Addressing these disparities, future research should
delve into sex-specific differences in miR-325, explore the
relationship between miR-325 and resistance to various anticancer
drugs, and investigate how abnormal miR-325 expression in tumors is
related to the efficacy of drug treatments. These areas of research
will provide a more comprehensive understanding of the role of
miR-325 in cancer, contributing to its potential as a robust
biomarker in diagnosis, treatment and prognosis across diverse
cancer types.
The present study comprised a comprehensive
examination of miR-325, offering a review that highlights its
potential as a potential focal point in cancer research. The review
not only identified the promise of miR-325, but also provided
valuable insights and directions for subsequent investigations into
its various facets. Simultaneously, it addressed existing
controversies and shortcomings within the current landscape of
miR-325 research. Future endeavors in this field may concentrate on
elucidating the aberrant molecular regulation of miR-325,
identifying its molecular mechanisms associated with antitumor drug
resistance and efficacy. An intriguing aspect is the chromosomal
location of miR-325 on the X chromosome. Nevertheless, the existing
literature has only described sex differences in miR-325 expression
in specific tumor types, signifying a lack of emphasis on
sex-specific cell line selection in ongoing research. To correct
for this, forthcoming studies should aim to amass gene expression
profiles from patient tissues of diverse sexes, integrating
comprehensive statistical analyses with clinical data from both
male and female patients with cancer. Such an approach promises to
establish a robust theoretical foundation for the clinical
application of miR-325 in tumor research.
Acknowledgements
Figs. 1, 3 and 4A
were created with BioRender.com.
Funding
The study was supported by the National Natural Science
Foundation of China (grant no. 32100521) and the Natural Science
Foundation of Zhejiang Province (grant no. LQ22C060001).
Availability of data and materials
Not applicable.
Authors' contributions
ZF, YaZ, YiZ, ZZ and YY collected and analyzed the
literature, drafted the figures and wrote the paper. CY, JD and SD
conceived and revised the article, and gave the final approval of
the submitted version. All authors have read and approved the final
version of the manuscript. Data authentication is not
applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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