Tumor metastasis is a hallmark of tumor development
and progression. Tumor metastasis involves the detachment of tumor
cells from the primary site through a series of biological
processes, including local infiltration, entry into the vascular
system, circulation, colonization of secondary tissues or organs,
and the formation of secondary tumors (1-4).
This complex process of tumor invasion and metastasis involves
multiple factors, including changes in the tumor microenvironment,
epithelial-mesenchymal transformation (EMT), tumor hypoxia,
neovascularization, decreased intercellular adhesion, cytoskeleton
remodeling, extracellular matrix degradation, and the formation of
cellular pseudopods and protuberances (5,6).
Although advances in existing treatments have improved survival
rates for some patients with cancer, distant metastasis remains a
major challenge (7,8). Once metastasis occurs, long-term
survival markedly decreases, and numerous patients succumb to the
disease shortly thereafter (9).
Tumor metastasis is one of the most important contributors to
cancer-related mortality and is a major obstacle in effective
clinical management (10).
Therefore, there is an urgent need to identify metastasis-specific
biomarkers and to explore the underlying molecular mechanisms.
Among numerous pathways, the ras homolog family
(Rho) and Rho-associated coiled-coil containing protein kinase
(ROCK) signaling pathway serves a key role in tumor metastasis.
This signaling pathway regulates cytoskeletal remodeling by
modulating myosin and actin activity, establishing cell polarity,
and organizing intermediate filaments. This pathway also
contributes to tumor cell proliferation, contraction, migration,
adhesion and cell-matrix interactions (11). The most widely studied Rho GTP
enzymes include Rho, Ras-related C3 botulinum toxin substrate (Rac)
and cell division cycle 42 (Cdc42) (12,13). These receptor proteins initiate
cytoskeleton reorganization and regulate downstream effectors that
affect tumor cell migration (14). Furthermore, the Rho/ROCK pathway
can regulate HIPPO/yes-associated protein (YAP) signaling by
modulating the actinomycin skeleton, with YAP acting as a
mechanical sensor that alters gene expression in response to
cytoskeleton dynamics (15). The
cytoskeleton, a dynamic network of protein fibers in eukaryotic
cells, serves an important role in cell division, intracellular
transport, motility and shape maintenance (16,17). The cytoskeleton comprises three
main components: Microfilaments, microtubules and intermediate
filaments (18). Microfilaments
are primarily involved in cytokinesis, cell motility and the
formation of intracellular stress fibers. Microtubules maintain
cell morphology, resist compression and facilitate intracellular
trafficking. Intermediate filaments provide mechanical stability
and coordinate cell migration. Together, these three cytoskeletal
components coordinate cellular integrity and ensure the smooth
progression of several biological functions, such as maintaining
cell morphology (16), material
transport (19) and cell
movement (20). Microtubules
serve a crucial role in cancer progression and metastasis (21,22). Microtubule-targeting agents have
emerged as promising tools to disrupt cancer cell activity and
inhibit metastasis (23,24).
Some antibody-drug conjugates, especially those
combined with microtubule-targeting compounds, have yielded
encouraging effectiveness in reducing tumor burden at metastatic
sites (25,26). Nestin, an intermediate filament
protein, is upregulated in several tumors, including pancreatic and
prostate cancer, malignant melanoma, and glioma, and is associated
with tumor aggressiveness, metastasis and poor prognosis (27,28).
Long non-coding RNAs (lncRNAs) were first identified
in the nucleus and cytoplasm of eukaryotic cells (29). Most lncRNAs lack a fully
functional open reading frame; however, previous studies have shown
that a few lncRNAs can encode a small number of functional short
peptides (30-32). Based on their location in the
genome, lncRNAs have been classified into five categories: Sense,
antisense, bidirectional, intergenic and intronic lncRNAs (33,34). Functionally, lncRNAs can be
classified into four types: Signaling, decoy, guide and scaffold
lncRNAs (35). Signaling lncRNAs
can be used as marker signals in different temporal spaces,
developmental stages and gene expression regulation (36). For example, there are three
common signaling lncRNAs: Air, Kcnq1ot1 and Xist. They mediate the
transcriptional silencing of multiple genes by interacting with
chromatin and recruiting chromatin modification mechanisms
(37). Guide lncRNAs can guide
the localization of ribonucleoprotein complexes to specific
targets. For example, the lncRNA COLDAIR can guide the polycomb
repressive complex 2 (PRC2) complex to serve a key biological role
in the chromatin of the floral repressor, flowering locus c
(38). Traditionally, proteins
have been important players in various types of scaffold complexes
(39). However, it has been
shown that lncRNAs can also serve as central platforms for the
assembly of relevant molecular components in several biological
signaling processes, and this precisely controlled property is
essential for precise control of the specificity and dynamics of
intermolecular interactions and signaling events (40). lncRNAs have been confirmed to be
associated with various cancer types, including colorectal,
gastric, hepatocellular and esophageal cancer (41-44). For example, lncRNA CCAT1 and
HOTAIR in the plasma of patients with colorectal cancer (CRC) have
been shown to serve as biological markers in CRC screening
(41). Aberrant expression of
three lncRNAs (POU3F3, SPRY4-IT1 and HNF1A-AS1) has been detected
in the sera of patients with oesophageal cancer. Notably, the
combined use of the three could effectively detect the early
development of esophageal cancer (44). lncRNAs also serve key roles in
tumor metastasis. lncRNA HIF1A-AS2 can promote the proliferation
and invasion of triple-negative breast cancer (TNBC) cells
(45). Compared with those in
normal lung tissue, lncRNA MALAT1 expression levels are elevated in
lung cancer, and abnormal MALAT1 expression can induce EMT to
further promote brain metastasis in lung cancer (46). With the continuous development of
high-throughput sequencing, numerous lncRNAs have been identified
due to their specific expression in tumor metastasis, and as
molecular biomarkers for tumor metastasis and potential therapeutic
targets for several tumors (47-49). For instance, Zhang et al
(50) developed a novel
computational framework employing six machine learning algorithms
to comprehensively analyze transcriptomic data from purified immune
cells, glioblastoma cell lines and bulk glioblastoma tissue. This
framework was utilized to screen for tumor-infiltrating immune
cell-associated lncRNAs predictive of prognosis and response to
immunotherapy in patients with glioblastoma.
In summary, among the multiple complex mechanisms of
tumor metastasis, lncRNAs are emerging as important modulators of
cytoskeleton dynamics, and likely affect tumor cell metastasis by
directly binding to cytoskeleton-related proteins or by indirectly
regulating key molecules in the Rho/ROCK signaling pathway. The
present review aims to explore the molecular mechanisms through
which lncRNAs mediate the Rho/ROCK signaling pathway during tumor
metastasis. An improved understanding of these interactions between
lncRNAs and the Rho/ROCK signaling pathway may provide novel
strategies for the early diagnosis and targeted treatment of
metastatic tumors.
The majority of the human genome (76-97%) is
transcribed into RNAs that are not translated into proteins, and
are referred to as non-coding RNAs (ncRNAs) (51). Taking 200 nt as the threshold,
ncRNAs are classified into two categories: Short ncRNAs (<200
nt) and lncRNAs (>200 nt) (52). According to their genomic
proximity to neighboring transcripts, lncRNAs can be classified
into four categories: i) Intergenic lncRNAs, which are located
between two protein-coding transcripts; ii) intronic lncRNAs, which
are present in the introns of coding transcripts; iii)
sense/antisense strand lncRNAs, which have overlapping parts with
introns and exons of different coding transcripts; and iv)
bidirectional lncRNAs, which share a promoter and are transcribed
from both sense and antisense directions of transcription start
areas (53). lncRNAs are
transcribed by polymerase II (54). Similar to mRNA, most lncRNAs
undergo 5' end capping, polyadenylation and splicing. They are
different in that the number of lncRNAs in exons is lower than that
in mRNA; therefore, lncRNAs are evolutionarily conserved to a
certain extent. Secondary and advanced structures are the most
important features of lncRNAs. lncRNAs form secondary structures,
including double helices, hairpin loops, protrusions and
pseudoknots, as well as tertiary structures with non-Watson-Crick
base pairs and more advanced structures. These structures form the
basis for the biological functions of lncRNAs. lncRNAs are unevenly
distributed in the nucleus and cytoplasm (55); however, the specific localization
of lncRNAs in the cytoplasm or nucleus, and the factors determining
such localization have not been fully confirmed (56).
In the whole genome, 50-70% of genomic DNA can be
transcribed; however, <2% of this is ultimately translated into
proteins (57), and the vast
majority of the remaining transcripts are transcribed into
non-coding ncRNAs. Although not translated, previous studies have
shown that ncRNAs are widely involved in various biological
processes of organisms (34,58-60). Compared with mRNAs, lncRNAs have
higher spatial and temporal specificity and lower interspecies
conservation, and they serve an essential role in regulating
chromatin dynamics (61,62), gene expression (63), cell proliferation (64), cell differentiation (65) and development of organisms
(63). One of the most important
functions of lncRNAs is the regulator of transcription (66,67). Among the identified action modes,
signaling, decoy, scaffolding and guidance are the most frequent
modes of action of lncRNAs in the cell (68). The main function of signaling
type lncRNAs is to regulate transcription as a molecular signal in
response to various stimuli, while the chromatin state of
regulatory elements can be further inferred from the expression of
related lncRNAs (36). In
addition, cellular stimulation can affect the transcriptional
expression of lncRNAs, which can perform regulatory functions to
affect the biological processes of organisms (69). Therefore, their production and
presence can be used as an indicator of transcriptional activity.
For example, DNA damage can induce the transcription of lncRNA
PANDA in a p53-dependent manner, which acts to limit the expression
of pro-apoptotic genes and arrest the cell cycle after interacting
with transcription factors (70). In an experiment involving the
induction of somatic cell reprogramming in pluripotent stem cells,
Loewer et al (71)
demonstrated that a large number of lncRNAs were aberrantly
expressed during this process. Among them, lncRNA RoR could
directly regulate the pluripotency factors OCT4, SOX2 and Nanog,
and served a role as a signaling molecule in the pluripotency and
reprogramming of stem cells. Decoy lncRNAs can directly bind
regulatory molecules such as transcription factors or RNA-binding
proteins, thereby sequestering them and blocking their activity and
downstream signaling pathways (72,73). For example, lncRNA PANDA inhibits
the expression of apoptotic genes by directly binding to nuclear
transcription factor Y subunit α, thus arresting the cell cycle
(74). Scaffold lncRNAs can
serve as molecular scaffolds that guide the assembly of protein
complexes onto target genes (75). For example, HOTAIR serves as a
molecular scaffold that links and targets the PRC2 and the lysine
specific demethylase 1 histone-modifying complexes, thereby
coordinating H3K27 methylation and H3K4 demethylation to reprogram
chromatin states (76). Guide
lncRNAs perform a 'guide-like' function, interacting with
ribonucleoprotein particles and taking them to specific target
genes, and serve the roles of cis-guides and trans-guides (77). In addition, some studies have
shown that a small number of lncRNAs can encode short peptides that
further function in the organism (78-80). With the widespread application of
next-generation sequencing technologies in different tumors, the
mystery of lncRNAs has been gradually unraveled. Thousands of
lncRNAs are aberrantly expressed in various tumors, suggesting that
they may serve an important role in the disease process of tumors
(81). The validated mechanisms
of lncRNAs in tumors are acting as competing endogenous RNAs
(ceRNAs), participating in chromatin remodeling, regulating
chromatin interactions and acting as natural antisense transcripts
(82). lncRNA HOTAIR is
dysregulated in a variety of cancer types (76,83,84), such as oral squamous cell
carcinoma (OSCC), hepatocellular carcinoma (HCC) and breast cancer.
Wu et al (76) found that
HOTAIR binds with EZH2 and H3K27me3 to form a complex, which can
bind to the promoter region of E-cadherin to regulate its
expression, thereby affecting OSCC metastasis. Recent studies have
revealed that lncRNAs can be encapsulated in exosomes, and
transferred from donor cells to recipient cells in the tumor
microenvironment by the fluid circulation, thereby regulating
several phenotypes of tumor processes (85,86), including malignant proliferation
and invasive metastasis of tumor cells, radiotherapy resistance of
tumor cells, formation of the tumor microenvironment and internal
angiogenesis. For example, Zhang et al (87) reported that exosomal lncRNA
MALAT1 was differentially expressed in non-small cell lung cancer
(NSCLC), high exosomal MALAT1 expression could promote metastasis
in NSCLC and the expression levels of MALAT1 were closely
associated with lymph node metastasis in patients with NSCLC. In
addition, exosomal lncRNAs released into the tumor microenvironment
have the potential to become tumor markers due to their specificity
and sensitivity (88-90).
The Rho/ROCK signaling pathway consists of the
Rho-GTPase family and its downstream effector ROCK (91-93) (Fig. 1). Rho GTPases are members of the
Ras superfamily of small GTP-binding proteins and contain >20
Rho proteins that can be broadly classified into the following five
groups based on their primary sequence and functional type: Rho,
Rac, Cdc42, Rho Family GTPase (Rnd) and Rho-related BTB
domain-containing subfamilies (92). Among these, the Rho, Rac and
Cdc42 subfamilies are the most intensively investigated and best
characterized functionally. The Rho subfamily includes RhoA, RhoB
and RhoC, which are very similar in sequence, and because they
share the same set of effectors, the mode of action of the three is
presumed to be similar (94).
RhoA, RhoB and RhoC have two different states in organisms
(inactive GDP-bound and active GTP-bound forms); the molecules
cycle between the two states. The transition from the inactive
GDP-bound form to the active GTP-bound form is catalyzed by the
diffuse B-cell lymphoma family of RhoGTP guanine nucleotide
exchange factors (95). By
contrast, the transition from the active to the inactive state is
mediated by intrinsic GTPase hydrolysis stimulated by Rho
GTPase-activating proteins (96). In the active state, Rho proteins
act on >60 downstream targets, including ROCK, mammalian homolog
of Drosophila (mDia), Par6B, p21 (RAC1) activated kinase 4
and Wiskott-Aldrich syndrome proteins (97). Activation of RhoGTPase ultimately
leads to the remodeling of the cytoskeleton and changes in other
fundamental processes, such as cell division, adhesion and
migration (98,99). The ROCK family consists of two
structurally similar isoforms, ROCK1 and ROCK2. Both kinases share
>30 direct downstream substrates, including myosin
phosphatase-targeting subunit 1, myosin light chain (MLC) and LIM
domain kinase, in addition to containing an N-terminal catalytic
kinase structural domain, a central coiled-coil structural domain
and a C-terminal PH structural domain (100). In Rho/ROCK signaling, Rho
(RhoA/RhoC) activates Rho-related kinases (ROCK1/ROCK2) by binding
to their C-terminal. ROCK regulates key proteins in the
cytoskeleton by mediating the phosphorylation of MLC, and
activating Lin-11, Isl1 and MEC-3 (LIM) structural domain kinases,
which are widely involved in basic cellular functions, including
adhesion, migration, contraction, proliferation and apoptosis
(101).
The vast majority of cellular activities are
directly or indirectly influenced by Rho family proteins. Rho
family proteins regulate the actin cytoskeleton to control cell
morphology, and serve an important role in cell polarity,
endocytosis, vesicle trafficking, adhesion and migration (13). RhoA interacts with effectors at
the cell membrane (102). RhoA
mediates the formation of myosin bundles and stress fibers
(103), and serves an important
role in membrane folding and lamellipodia formation (104). RhoB is present on the outer
membranes of multivesicular bodies and in the plasma membrane and
serves a role in vesicle transport (105). RhoC is mainly located in the
plasma membrane or cytoplasmic matrix, and mainly regulates the
activity of actin and myosin and limits lamellipodial broadening
(106). The Rac subfamily
primarily stimulates the formation of lamellar pseudopods, membrane
folds and invasive foot types (107). Rac1 is commonly distributed in
tissues, and mainly regulates the formation of scaffolding
proteins, membrane ruffles and lamellipodia (108). Rac2 is confined to
haematopoietic tissues, and regulates cell adhesion and
participates in cellular immune synapse formation (109). Rac3 is a neuron-specific
protein that is important for regulating autophagy, inducing the
formation of invadopodia and degrading extracellular matrix
(110,111) The Cdc42 subfamily mediates the
formation of a third actin-based structure, the filopodia, by
binding to Wiskott-Aldrich syndrome protein or neural
Wiskott-Aldrich syndrome protein (112). Additionally, Cdc42 serves an
important role in cell polarization (113). Rho downstream effectors include
ROCK and p140mDia (114). The
ROCK family belongs to the AGC family of serine/threonine protein
kinases. ROCK1 serves a key role in the formation of actin bundles,
actin contractility and stress fibers by mediating the
cross-linking of myosin, while ROCK2 is required for phagocytosis
and cell contraction and is important in stabilizing the
cytoskeleton (115). The
Rho/ROCK signaling pathway serves a key role in central nervous
system disorders, pulmonary hypertension and other diseases
(116,117).
Metastasis, the spread of malignant cells to distant
organs, represents the ultimate stage of cancer progression and
remains a leading cause of cancer-related deaths (107). The majority of cancer deaths
result not from the primary tumor but from the secondary lesions in
vital organs. This complex process includes a series of sequential
events: Primary tumor cells gradually acquire invasive abilities,
spread through blood or lymphatic vessels (or directly invade
adjacent tissues), and finally colonize and proliferate in distant
organs (118). Although
different cancer types and molecular subtypes exhibit marked
differences in metastasis-driving genes, microenvironmental cues
and anatomical dissemination routes, several core cellular
processes are shared (119).
Among these, cell migration is a core process that is universally
present across various tumor types (120). Therefore, targeting the
signaling networks that regulate cell motility could offer an
effective strategy for the management of metastasis in multiple
cancer types (121-123).
The Rho GTPase family functions as a core molecular
switch regulating cytoskeletal dynamics and cell movement (124). Growing evidence has highlighted
the critical role of this family in tumor invasion and metastasis
(123,125). For example, Zhang et al
(126) demonstrated that
inhibition of RhoA suppressed proliferation in gastric cancer
cells. In breast cancer, altered Rho GTPase signaling disrupts
cytoskeleton architecture in cancer cells, and serves a critical
role in cell motility, migration and invasion (127). In cholangiocarcinoma, tumor
cells recruit cancer-associated fibroblasts by secreting PDGF-D,
which stimulates fibroblast migration by upregulating
platelet-derived growth factor receptor β and Rho GTPase, and
activating the JNK pathway (128). With the emergence of
pharmacological agents targeting the Rho/ROCK signaling axis,
particularly selective ROCK inhibitors, this pathway has become a
promising target for the development of antimetastatic treatments
(123).
The subcellular localization of lncRNAs is closely
related to their biological functions (129). Unlike the relatively discrete
cytoplasmic distribution of mRNAs, most lncRNAs are found in both
the nucleus and cytoplasm, with the cytoplasm often being their
primary site of localization (130,131). Structurally, lncRNAs contain
intronic and other non-coding elements that provide potential
binding sites for miRNAs. Through sequence complementarity, lncRNAs
can bind intracellular miRNAs and weaken or block their ability to
suppress target genes (24).
This competitive binding between lncRNAs and miRNAs forms ceRNA
networks, indirectly affecting components of the Rho/ROCK signaling
pathway (132).
Several studies have demonstrated that lncRNAs
influence components of the Rho/ROCK signaling pathway via ceRNA
networks, ultimately modulating tumor cell proliferation, invasion,
migration and apoptosis (38,133-181) (Table I). For example, the expression of
lncRNA DAPK1 is reduced in pancreatic cancer tissues, where it
modulates invasion and migration by sponging miR-182 to regulate
ROCK1 expression (133).
Similarly, Liu et al (134) demonstrated that lncRNA ZFAS1
promoted pancreatic cancer metastasis by acting as a sponge for
miR-3924 and subsequently regulated the RhoA/ROCK2 pathway to serve
a pro-metastatic role in pancreatic cancer. Furthermore, lncRNA
NORAD facilitates EMT in pancreatic cancer by binding miR-125a-3p,
which regulates the expression of the downstream effector molecule
RhoA (135). Liu et al
(136) reported that lncRNA
NEAT1 acted as a ceRNA by sponging miR-382-3p and upregulating
ROCK1 in ovarian cancer (OC), and thus, enhanced the metastatic
potential. NEAT1 also inhibits the progression of lung
adenocarcinoma by sponging miR-490-3p, leading to suppression of
the RhoA/ROCK pathway (137).
Furthermore, Zhang et al (138) found that lncRNA LINC01087
promoted lung adenocarcinoma progression by regulating the
miR-514a-3p/CEP55/RhoA/ROCK1 axis.
In osteosarcoma, the lncRNA DANCR sponges miR-335-5p
and miR-1972, leading to an increase in ROCK1 expression, which
promotes metastasis (139).
Similarly, Shao et al (140) demonstrated that, in
osteosarcoma, lncRNA ZNF281 suppressed invasion by upregulating
miR-144 expression, thus suppressing ROCK1 expression. Furthermore,
in osteosarcoma, lncRNA SNHG1 is overexpressed and promotes cell
metastasis by altering apoptosis and the cell cycle; functional
experiments have shown that SNHG1 regulated ROCK1 expression by
sponging miRNA-101-3p (141).
Additionally, Wang et al (142) reported that SNHG5 functioned as
a ceRNA for miR-26a and activated the ROCK signaling pathway
through the miR-26a/ROCK1 axis to promote osteosarcoma cell
malignancy. In HCC, lncRNA CDKN2BAS is upregulated in metastatic
tissues and sponges miR-153-5p to increase the expression of Rho
GTPase activating protein 18 (ARHGAP18), thus enhancing cell
migration (143). Furthermore,
lncRNA LINC00607 promotes HCC cell proliferation, migration and
invasion through the miR-584-3p/ROCK1 axis (144). Thus, cytoplasmic lncRNAs
regulate tumor metastasis by forming ceRNA networks with miRNAs
that target Rho/ROCK signaling components.
In addition to sponging miRNAs by acting as ceRNAs,
lncRNAs can also directly bind to specific proteins, including
those involved in the Rho/ROCK signaling pathway, and regulate
tumor metastasis (182)
(Fig. 2). In bladder cancer,
lncRNA lnc00892 is downregulated and is positively associated with
the prognosis of patients with bladder cancer. Mechanistically,
lnc00892 binds to c-JUN, a component of the activating protein-1
transcriptional complex, and reduces nucleolin transcription and
affects the stability of RhoA/RhoC mRNAs, which suppresses bladder
tumor metastasis (183). In
NSCLC, lncRNA NORAD inhibits metastasis by binding to and
interfering with CXC chemokine receptor 4, which in turn suppresses
the RhoA/ROCK signaling pathway (184). Similarly, in bladder cancer,
overexpressed lncRNA KTN1-AS1 recruits EP300, leading to histone H3
lysine 27 acetylation at the KTN1 promoter region. This epigenetic
regulation ultimately affects bladder cancer growth and metastasis
by mediating the Rho GTPase signaling pathway through Rac1, RhoA
and Cdc42 (185). In HCC,
overexpression of lncRNA SchLAH (also referred to as BC035072)
inhibits distant metastasis. Functional experiments have shown that
SchLAH interacts with DNA/RNA-binding protein-fusion sarcoma,
regulating the mRNA expression of downstream effector molecules
RhoA and Rac1 (186). Dai et
al (187) used mass
spectrometry and reported that a total of 93 upregulated and 352
downregulated lncRNAs were identified in patients with bladder
cancer; downregulated lncRNA MUC20-9 bound directly to ROCK1 and
inhibited tumor growth, migration and invasion. MUC20-9 was
considered to be a potential therapeutic target for bladder cancer.
In OC, lncRNA ABHD11-AS1 is upregulated and facilitates metastasis
by directly binding to RhoC (188). Similarly, Wu et al
(189) identified a novel
lncRNA, MER52A, which was highly expressed in HCC tissues.
Mechanistically, MER52A promoted HCC cell invasion and metastasis
by stabilizing P120-catenin, thus activating Rac1 and Cdc42, key
downstream Rho-GTPases. Furthermore, high MER52A expression was
strongly associated with advanced TNM stage, poor differentiation
and reduced overall survival of patients with HCC. In osteosarcoma,
AFAP1-AS1 is also highly expressed and directly interacts with RhoC
and activates the RhoC/ROCK1/p38MAPK signaling pathway, which in
turn exerts oncogenic effects (190).
Tumor metastasis remains a major contributor to
treatment failure and cancer-related mortality (191). Numerous patients with cancer
are diagnosed at intermediate or advanced stages, when clinical
symptoms appear; consequently, their prognosis is poorer than that
of patients diagnosed earlier (192). Epidemiological data indicate
that ~90% of cancer-related deaths are due to tumor metastasis
(193). Therefore, identifying
novel and reliable biomarkers and therapeutic targets associated
with the metastatic potential is critical to improve early
detection and intervention strategies.
Rho/ROCK signaling pathway-associated lncRNAs have
increasingly been explored and defined. These lncRNAs not only
serve an important role in tumor metastasis but also have a close
relationship with the clinical characteristics of patients with
tumors (133,135,136,140,145,151,153,159,165, 166, 171,173,179,180,188,189,194-204) (Table II). A previous study has
demonstrated that lncRNA AFAP1-AS1 was upregulated in patients with
HCC, and was associated with pathological stage and lymphovascular
interstitial infiltration (194). Multifactorial analysis revealed
that AFAP1-AS1 was an independent predictor for overall survival,
supporting the hypothesis that AFAP1-AS1 is a potential therapeutic
target for HCC. Similarly, lncRNA LOC284454, upregulated in
nasopharyngeal carcinoma (NPC), promotes migration and invasion by
regulating the cytoskeleton-related Rho/Rac signaling pathway, and
is strongly associated with poor prognosis in patients with NPC
(195). Hu et al
(196) demonstrated that
ARHGAP42, another pro-metastatic lncRNA in NPC, was associated with
shorter metastasis-free survival. In vitro experiments
demonstrated that ARHGAP42 promoted the metastasis and invasion of
NPC cells, suggesting that it may serve as a tumor migration
marker, a prognostic factor or a therapeutic target for patients
with NPC. In gliomas, lncRNA LINC00346 is upregulated and is
strongly associated with both disease-free and overall survival,
suggesting its usage as a potential therapeutic target and
therapeutic candidate (159).
lncRNA MAGI2-AS3 expression is downregulated in serum samples from
patients with HCC with distant metastases compared with in those
from non-metastatic patients. Overexpression of MAGI2-AS3
suppresses cell invasion and migration by modulating ROCK2, while
its downregulation is associated with distant recurrence following
surgical resection (197). In
papillary thyroid carcinoma (PTC), lncRNA DLEU1 expression is
elevated and associated with lymph node metastasis and clinical
stage (145). Follow-up
bioinformatics and dual luciferase reporter gene analysis revealed
that DLEU1 affects PTC proliferation, survival and metastasis by
regulating miR-421 binding to the 3' untranslated region of ROCK1
in TPC-1 cells. Furthermore, lncRNA CDKN2B-AS1 expression is
elevated in laryngeal squamous cell carcinoma (LSCC) tissues, and
its high expression is positively associated with overall survival,
lymph node metastasis and the clinical stage of patients with LSCC
(198).
Rho/ROCK signaling pathway-associated lncRNAs may
also serve as liquid biopsy biomarkers. Liquid biopsy, an
innovative technology, has opened novel pathways for the early
diagnosis and prognostic evaluation of cancer. Compared with
traditional tissue biopsies, liquid biopsy enables real-time
monitoring of disease progression and therapeutic responses
(205). Liquid biopsy platforms
can simultaneously detect multiple circulating biomarkers,
including circulating tumor cells (CTCs), circulating tumor DNA,
exosomes, tumor-educated platelets and circulating free RNA. Among
these, exosomes, nanosized extracellular vesicles (30-150 nm),
serve crucial roles in intercellular communication and carry active
molecules such as proteins and nucleic acids (DNA and RNA,
including lncRNAs) (206,207). Previous studies have shown that
several lncRNAs can be encapsulated in exosomes and transferred
from donor cells to recipient cells, where they regulate components
of the Rho/ROCK signaling pathway, thereby regulating cancer
progression and metastasis (154,208,209). For example, You et al
(154) demonstrated that
exosome-derived lncRNA LINC00161 sponged miR-590-3p to promote HCC
metastasis by activating the ROCK signaling pathway, suggesting
that LINC00161 may serve as a novel prognostic marker for HCC.
Furthermore, Ding et al (209) reported that CRC cell-derived
exosomal lncRNA BANCR promoted M2 macrophage polarization and
enhanced CRC cell proliferation and invasion via the RhoA/ROCK
pathway, with insulin like growth factor 2 mRNA binding protein 2
acting as a mediator. Together, these findings suggest that
Rho/ROCK pathway-associated lncRNAs, particularly those in
exosomes, are emerging as valuable molecular biomarkers with
potential applications in liquid biopsy-based diagnostics.
In addition to their diagnostic utility, Rho/ROCK
signaling pathway-associated lncRNAs represent potential
therapeutic targets for metastatic cancer (154,210) (Fig. 3). As shown in Fig. 3, You et al (154) established a xenograft model in
which tail-vein inoculation of HCC cells produced widespread
metastases; notably, tail-vein injection of HCC cells with stable
LINC00161 knockdown markedly attenuated both tumor initiation and
metastatic dissemination in vivo, indicating that LINC00161
silencing suppressed HCC tumorigenesis and metastasis. Horita et
al (210) reported that
lncRNA UCA1 is upregulated in OC and enhances oncolytic poxvirus
dissemination by modulating the Cdc42 signaling pathway, a key
regulator of cytoskeletal reorganization (210). Similarly, UCA1 sponges
miR-18a/miR-182 to regulate Cdc42/filopodia, thereby increasing
sensitivity to poxvirus-based virotherapy in CRC (169). Clinically, glucocorticoids,
such as dexamethasone and prednisolone, can be used in combination
with other chemotherapeutic agents for the treatment of hematologic
malignancies. In acute myeloid leukemia, lncRNA HOTAIRM1 promotes
glucocorticoid resistance by binding to the transcriptional
repressor region of ARHGAP18, which in turn activates the
RhoA/ROCK1 signaling pathway. This finding has implications for the
optimization of glucocorticoid-based leukemia treatment strategies
(211). In oral squamous cell
cancer, low expression levels of lncRNA LOC441178 are associated
with longer postoperative survival, suggesting a potential role as
a tumor suppressor and prognostic marker (212). In osteosarcoma, lncRNA CCHE1
expression is higher in patients with distant recurrence after
surgery and associated with ROCK1 expression, suggesting that CCHE1
may help guide subsequent chemotherapy or radiotherapy (213). Rho-GTPases and their downstream
signaling molecules have been shown to serve a key role in
regulating tumor angiogenesis, invasion, metastasis and EMT
(214-216). Targeting EMT is considered a
relatively promising strategy to inhibit metastasis and improve the
survival rate of patients with cancer (191). lncRNA AFAP1-AS1 expression is
upregulated in osteosarcoma, and is involved in the growth and
metastasis of osteosarcoma by interacting with RhoC and regulating
EMT. Therefore, AFAP1-AS1 inhibitors may serve as therapeutic
agents in osteosarcoma (190).
Furthermore, targeting lncRNAs involved in drug resistance has also
shown promise. In cholangiocarcinoma, lncRNA CCAT1 modulates EMT
via ROCK2. CCAT1 knockdown increased the susceptibility of an
erlotinib-resistant cholangiocarcinoma cell line xenograft to
erlotinib in vivo, suggesting that targeting the
miR-181a-5p/ROCK2 signaling axis could overcome resistance
(217). Using a small-molecule
microarray, Abulwerdi et al (218) identified several chemotypes
that bind the MALAT1 element for nuclear expression triplex-binding
chemotypes (referred to as MALAT1-IN-1). Notably, compounds 5 and
16 lowered MALAT1 RNA levels and suppressed branching morphogenesis
in mammary tumor organoids, establishing triplex-targeting
scaffolds as preclinical leads for anticancer therapeutics and
molecular probes.
Inhibitors targeting the Rho/ROCK signaling pathway
have gained attention in drug research for tumor-targeted therapy
(91). These inhibitors of the
Rho/ROCK pathway are divided into three categories: Inhibitors of
ROCK, geranylgeranyltransferase-1 and
3-hydroxy-3-methyl-glutaryl-CoA reductase (219-222). MBQ-167, a newly developed Rac
and Cdc42 inhibitor, has been shown to inhibit p21 activated
protein kinase signaling, metastatic cell migration and mammosphere
growth in TNBC. Its short half-life and low toxicity make this
inhibitor a promising candidate for future TNBC therapy (219). NecroX-5 has demonstrated
anti-metastatic effects in lung cancer, breast cancer and melanoma
models by suppressing the expression of Cdc42, Rac1 and RhoA
(220). NSC23766, the first
Rac1-specific inhibitor, blocks Rac1 activation by targeting the
guanine nucleotide exchange factors. NSC23766 inhibits the invasion
and migration of human HCC by interfering with the Rac1/JNK or LIM
and cysteine-rich domains 1-Rac1 pathways (221). Inhibition of Rac1 by NSC23766
affects the proliferation and migration of NSCLC (222). Overall, Rho/ROCK pathway
inhibitors represent a promising strategy to overcome drug
resistance and prevent tumor metastasis. Therefore, the development
of Rho/ROCK pathway inhibitors remains a key clinical strategy in
cancer therapy.
Tumorigenesis is a complex process that involves
multiple malignant phenotypes, among which metastasis is a leading
contributor to cancer-related mortality. Tumor metastasis involves
a series of complex pathophysiological changes, with cytoskeletal
reorganization serving a critical role in cancer cell invasion and
migration. Among the classical signaling pathways implicated in
cytoskeletal reorganization, the Rho/ROCK signaling pathway has
attracted considerable attention. Accumulating evidence has also
demonstrated that lncRNAs regulate tumorigenic processes, including
proliferation, migration, metastasis and resistance to radiotherapy
(198,223). With the development of
high-throughput sequencing and related technologies, an increasing
number of lncRNAs have been identified that interact, either
directly or indirectly, with key cytoskeletal regulators such as
ROCK1 and ROCK2, mediating tumor metastasis by altering the
three-dimensional structure of cancer cells and regulating the
reconstruction of the cytoskeleton. As research continues to
uncover the specific mechanisms and clinical implications of
Rho/ROCK signaling pathway-associated lncRNAs, several promising
applications have emerged. First, Rho/ROCK signaling
pathway-associated lncRNAs may serve as pathological and liquid
biopsy markers for patients with tumors. Unlike protein-based
pathological tissue biomarkers, which often reflect downstream
changes, the aberrant expression of lncRNAs often occurs earlier
than changes at the protein level, providing greater tissue
specificity and expression sensitivity for early cancer diagnosis
(224,225). Their tissue specificity,
dynamic expression and distinct subcellular localization make them
particularly suitable for precise classification and prognosis
(226). While tissue biopsy
remains the gold standard for diagnosing tumor subtypes and grades,
its invasiveness limits its applications for dynamic monitoring of
disease progression. Liquid biopsy, on the other hand, offers a
minimally invasive monitoring strategy by analyzing circulating
tumor components in bodily fluids such as blood and urine (227). In addition, circulating lncRNAs
exhibit high stability and resistance to nuclease degradation,
offering advantages over other biomarkers such as cell-free DNA
(including circulating tumor DNA), CTCs and exosomal RNA (228). Several lncRNAs, including those
detectable in liver, colorectal, gastric and prostate cancer, have
already shown promise as reliable diagnostic and prognostic markers
(229-231). Second, next-generation
sequencing, combined with artificial intelligence (AI) and machine
learning, has accelerated the collaborative development of basic
cancer research and clinical oncology (232-234). Tumor genomic databases
constructed from high-throughput sequencing systematically analyze
disease-specific expression profiles and tumor microenvironment
characteristics. Researchers can leverage advanced machine learning
algorithms to deeply mine sequencing data, successfully identifying
functional lncRNAs that can serve as biomarkers for personalized
treatment decisions or prognostic predictions. Deep learning
algorithms enable the precise identification of Rho/ROCK signaling
pathway-associated lncRNAs, as well as the prediction of their
interacting proteins and binding miRNAs, providing a novel strategy
for the development of cancer-specific diagnostic and prognostic
biomarkers. Third, despite the potential of RNA-based therapeutics,
clinical translation is challenged by issues such as target
specificity, low delivery efficiency and in vivo stability
(235). Notably, while a few
miRNA drugs have entered phase II/III clinical trials, the
development of inhibitors targeting lncRNAs remains in the
preclinical stage (236-238).
However, nanotechnology provides a promising strategy to overcome
these limitations. Nanomaterials can enable precise targeting at
the tissue and even subcellular levels, delivering complex
therapeutic molecules to key metastatic sites (such as lymph nodes,
liver and lungs) and specific subcellular regions (239). Advances in translational
medicine have focused on co-delivering lncRNA inhibitors with small
molecule drugs or immune checkpoint inhibitors via nanoparticle
systems, synergistically enhancing antitumor efficacy (240-243). Based on this research, the
future development of nanoparticle carriers encapsulating Rho/ROCK
signaling pathway-associated lncRNA inhibitors may improve the
prognosis of patients with metastatic cancer.
Nevertheless, existing research on Rho/ROCK
signaling pathway-associated lncRNAs still has several limitations.
First, although high-throughput studies have identified numerous
dysregulated lncRNAs in tumor tissues (244,245), the specific molecular
mechanisms by which Rho/ROCK signaling pathway-associated lncRNAs
influence metastasis require further elucidation. Second, Rho/ROCK
signaling pathway-associated lncRNAs may regulate gene expression
through multiple miRNA sponging interactions or binding proteins,
but the specific target axis may not be limited to one or two axes.
Third, some lncRNAs implicated in the Rho/ROCK signaling pathway
may also regulate other signaling cascades. In addition, the
Rho/ROCK signaling pathway mainly promotes tumor metastasis;
however, a study has reported that the Rho/ROCK signaling pathway
may induce apoptosis (246).
Street et al (247)
demonstrated that the ROCK inhibitor Y27632 could enhance the
survival of neuroblastoma cells. Therefore, future studies must
validate pathway specificity when proposing drug targets. Fourth,
whether Rho/ROCK signaling pathway-associated lncRNAs can be used
as therapeutic targets still requires further research at present.
Existing studies are only at the stage of animal experiments
(135,146,150,153,154), and there is still a long way to
go from basic research to clinical application. Therefore, the
relationship between Rho/ROCK signaling pathway-associated lncRNAs
and tumor metastasis needs to be further clarified. Fifth, although
the drug delivery systems of nanoparticle-based lncRNA inhibitors
show potential (239-241), further clinical validation is
needed to ensure their efficacy, safety and long-term effects of
the delivery of nucleic acids in humans.
In summary, lncRNAs associated with the Rho/ROCK
signaling pathway are emerging as key regulators of cytoskeletal
remodeling and tumor metastasis. Through interactions with miRNAs,
proteins and exosomal transport mechanisms, these lncRNAs regulate
key processes involved in cancer cell migration, invasion and
metastasis. They hold promise not only as novel biomarkers for
early cancer diagnosis but also as therapeutic targets to prevent
metastasis. Advances in high-throughput sequencing, AI-driven
bioinformatics and nanomedicine provide novel opportunities to
leverage lncRNAs in personalized treatment strategies and improve
prognostic predictions. However, further research is needed to
fully elucidate the mechanisms by which lncRNAs regulate the
Rho/ROCK pathway and to confirm their clinical applicability. The
present review highlights the growing potential of Rho/ROCK
signaling pathway-associated lncRNAs as promising diagnostic and
therapeutic targets, with the potential to improve the management
and prognosis of metastatic cancer.
Not applicable.
HN and XY performed the literature search. HN and
XY prepared the first draft of the manuscript. QC, XH and YH wrote
and edited the manuscript. HN and YH drew the figures. QH and CO
prepared the tables and were responsible for revising the
manuscript. CO obtained funding support. Data authentication is not
applicable. All authors reviewed the manuscript, and have read and
approved of the final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by the National Natural Science
Foundation of China (grant no. 82373062) and the Central South
University Innovation-Driven Research Programme (grant no.
2023CXQD075).
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