Esophageal cancer (ESCA) is a solid tumor and
frequently occurs in the digestive tract. It is highly invasive and
has a high incidence rate and mortality (1); its cancer mortality ranks sixth
worldwide and the overall 5-year survival rate is low (2–4); it is
estimated to be ~15–25% (4,5). According to histopathological results,
it can be classified into esophageal adenocarcinoma (EAC) and
esophageal squamous cell carcinoma (ESCC). Due to differences in
etiology and geographical incidence rate, EAC is common in the
Western population, while ESCC is prevalent in the Eastern
population (5–8). The incidence of ESCA is closely
associated with smoking, alcohol consumption, unhealthy dietary
habits and obesity (9). In China,
the incidence rate of ESCC is higher due to its early symptoms not
being obvious (10); therefore, the
majority of the patients have developed late-stage disease when
diagnosed, with low quality of life and poor prognosis (2). At present, the conventional clinical
treatment methods for ESCA are surgery, chemotherapy and
radiotherapy (11); however, with
the complex development of the disease, including invasion and
metastasis, as well as drug resistance and normal cell toxicity,
traditional treatment methods face significant challenges (12). In order to enhance treatment
effectiveness and improve the low survival rate, treatment methods
need to be constantly updated and strengthened, which requires an
urgent proposal of new strategies.
MicroRNAs (miRNAs/miRs) are a class of non-coding
conserved small-molecule RNAs with a length of ~20 nucleotides
(13). Mature RNA binds to the
corresponding mRNA molecule, regulates the relevant gene
expression, participates in the regulation of biological behaviors,
such as cell proliferation, differentiation, apoptosis and
metabolism, and plays a wide range of regulatory roles (13–18).
In cancer, certain miRNAs are often abnormally expressed and become
tumor promoters or suppressors (13,16,19–23).
Signal transduction and transcription activator 3 (STAT3) is a
widely studied crucial component that connects cellular signaling
and transcription (24), controls
multiple signaling pathways and acts as a hub gene (25). Abnormal expression of STAT3 can lead
to cellular dysfunction, development of diseases and various
malignant tumors in humans (26).
In tumor tissues, constitutively activated STAT3 can promote
multiple malignant behaviors of cancer cells (24,25,27–33).
Numerous studies have shown that miRNAs can participate in
regulating the STAT3 signaling pathway; furthermore, STAT3 can
modulate the expression levels of multiple miRNAs. MiRNAs and STAT3
interact via direct or indirect mechanisms, forming signaling
circuits that affect cellular balance (34–37).
With the continuous advancement in molecular biology
research, an accumulating number of studies have indicated that the
occurrence of cancer is related to unusual signaling routes within
cells. Furthermore, targeted therapy has become a method of
precision treatment for tumors (12). The STAT3 signaling pathway mediated
by miRNAs has been widely explored in various cancer types; e.g. in
gastric cancer (38), leukemia
(39), colorectal cancer (26) and ESCA (40). A review was conducted on the miRs
involved in the STAT3 signaling pathway in ESCA following a
literature search in the PubMed database using the key words
‘esophageal cancer’, ‘STAT3’ and ‘miRNA’. The present review
unveiled the complex pathogenesis behind ESCA by analyzing the
interaction between STAT3 and different miRNAs, as well as the
impact of miRNAs on the STAT3 signaling pathway (Fig. 1); it also reviewed the effects of
different miRNAs and the STAT3 signaling pathway on the
proliferation, invasion, metastasis, apoptosis, drug resistance and
immune escape of ESCA. Understanding the molecular mechanisms of
the interaction between miRNAs and STAT3 can provide favorable
conditions to identify potential therapeutic targets for ESCA and
develop novel anticancer drugs, laying a foundation for formulating
new clinical plans. This is of great significance for improving
disease prognosis and provides hope for the survival of patients
with ESCA.
The majority of the miRNAs associated with the STAT3
signaling pathway exert inhibitory effects on tumors, including
miR-124 (41,42), miR-125a-5p (43), miR-296-5p (44), miR-874-3p (45), miR-17-5p (46), miR-149-5p (47), miR-30b (48), miR-181c-5p (49), miR-494 (50), miR-495-3p (51) and miR-34a (52) (Table
I; Figs. 2 and 3).
As a highly conserved miRNA, miR-124 is a mediator
of the STAT3 signaling pathway, which inhibits cancer development;
it has been confirmed in various studies. Overexpressed miR-124 can
downregulate STAT3 and further inhibit the growth of bladder cancer
(53), colorectal cancer (54) and hepatocellular carcinoma (55). In ESCA, the expression levels of
miR-124 are significantly reduced, STAT3 is constitutively
activated and its content is negatively associated with miR-124.
Previous research studies have shown that miR-124 can directly
inhibit STAT3 and further hinder cell proliferation, invasiveness
and metastasis and aid the induction of apoptosis (41,42).
Similarly, upregulation of miR-125a-5p levels causes binding to
STAT3 and reduces STAT3 expression, leading to cell-cycle arrest
and prevention of cell growth in ESCC (43); miR-296-5p inhibits the occurrence of
ESCC by downregulating STAT3 levels (44). STAT3 is a direct functional target
of miR-874-3p in ESCC cells; following their combination, they can
form the miR-874-3p/STAT3 signaling axis to prevent the malignant
behaviors of tumor cells (45).
STAT3 is the direct downstream target of miR-17-5p, which binds to
STAT3 to reduce the proliferative, migratory and invasive
capacities of esophageal cancer cell line TE-1 (46).
In addition to the direct binding to STAT3, miRNAs
can indirectly mediate the STAT3 signaling pathway. MiR-149-5p
inhibits the expression of interleukin-6 (IL-6) at the
transcriptional and translational level. IL-6 is a general STAT3
activator (29,56) and overexpression of miR-149-5p can
suppress the abnormal proliferation, migration and invasion of ESCC
cells via the miR-149-5p/IL-6/STAT3 signaling pathway (47). Chromobox 3 (CBX3) is a member of the
chromobox protein family, which promotes the development of various
cancer types, including gastric cancer (57), breast (58) and pancreatic cancer (59). The Janus kinase (JAK)2/STAT3 is a
common signaling pathway found in various tumors (24,31,60–62).
CBX3 is a downstream target of miR-30b expressed in ESCC cells.
When the levels of miR-30b are reduced, the expression levels of
CBX3, phosphorylated (p-)JAK2 and p-STAT3 are markedly increased
and the JAK2/STAT3 signaling pathway is apparently active.
Therefore, upregulation of miR-30b expression can inhibit cancer
development via the miR-30b/CBX3/JAK2/STAT3 signaling axis
(48). MiR-181c-5p indirectly
controls ESCC by binding to LIM and the SH3 protein 1 (LASP1),
which can activate STAT3. MiR-181c-5p decreases STAT3 expression
and hinders cell proliferation, invasiveness and migration by
interacting with LASP1 (49).
MiR-494 can negatively regulate the expression of cyclin-dependent
kinase (CDK)6, which promotes cell-cycle progression (63). Upregulated miR-494 binds to CDK6 to
inhibit the downstream JAK2/STAT3 signaling pathway, resulting in
an antitumor effect (50). By
targeting Budding uninhibited by benzimidazoles 1 (BUB1), which can
directly upregulate the phosphorylation levels of STAT3, miR-495-3p
can also hinder the growth of ESCA via the miR-495-3p/BUB1/STAT3
signaling pathway (51). The
aforementioned miRNAs are upstream molecules of STAT3 and miR-34a,
an effective tumor suppressor, which can form a feedback loop with
STAT3 to inhibit ESCA. Programmed cell death-ligand 1 (PD-L1) and
IL-6 receptor (IL-6R) are targets in the loop and miR-34a
competitively blocks the binding of IL-6 to its receptor to inhibit
STAT3 activation. However, overactivated STAT3 can induce IL-6.
Ultimately, they can form the miR-34a/STAT3/IL-6R feedback loop and
increase miR-34a expression, which can hinder the progression of
ESCC (52). In addition, miR-34a
targets the E2F transcription factor 5, which can affect epithelial
mesenchymal transition (EMT) and inhibit migration of ESCC
(64). By inhibiting the
PI3K/AKT/mTOR signaling pathway, miR-34a can reverse radiation
resistance of ESCC and improve radiotherapy efficacy (65). Overexpressed miR-34a levels can also
control the expression of matrix metalloproteinase (MMP)-2 and
MMP-9 or bind to Yinyang-1 to inhibit ESCC metastasis and invasion
(66,67).
As an important coordinating factor, miR-126 binding
to different targets exerts a certain influence on ESCA. A previous
study indicated that overexpressed miR-126 can downregulate the
content of microtubule-associated protein 1 light chain 3β and
sequestosome 1 (p62) related to autophagy. STAT3 is a direct target
of miR-126 and its silencing leads to a decrease in autophagy;
therefore, miR-126 can bind to STAT3 and may activate it, which
further inhibits apoptosis and autophagy of the esophageal squamous
cell and promotes the development of ESCC (68). However, miR-126 has an inhibitory
effect on ESCC via integrating with vascular endothelial growth
factor-A (VEGF-A) (73) or insulin
receptor substrate-1 (IRS-1) and Golgi phosphoprotein 3 (GOLPH3)
(74) and it can also mediate the
PI3K/AKT (75) or the ADAM
metallopeptidase domain 9 (ADAM-9)/EGFR/AKT (76) signaling pathway to suppress the
progression of ESCC. In addition, miR-126-5p can influence the
proliferation and invasion of ESCC by negatively regulating CDK
(77). The different signaling
pathways involved in miR-126 have the opposite effect; therefore,
the definite role of miR-126 requires further exploration under
specific conditions in ESCA. Unlike miR-126, miR-4286 and
miR-106b-5p bind to downstream molecules to indirectly induce STAT3
activation. MiR-4286 targets inositol polyphosphate-4-phophatase
type IA and negatively regulates it to evoke the JAK/STAT3 pathway;
in this way, it indirectly facilitates ESCA (69). Furthermore, miR-4286 can be a member
of the miR spectrum that distinguishes ECA from Barrett's esophagus
(78). Overexpression of
cytoplasmic polyadenylation element binding protein 3 (CPBE3) can
hinder tumor migration, invasion, angiogenesis and STAT3 activity
and suppress EMT in ESCA. MiR-106b-5p can negatively regulate
CPBE3, thereby enhancing the activation of STAT3 and facilitating
EMT; this results in the formation of the miR-106b-5p/CPBE3/STAT3
signaling axis, which aids tumor growth (70).
MiR-181b and miR-19b-3p promote the development of
ESCA via feedback loops. In ESCA stem cells, the combination of
STAT3 and miR-181b promoter induces miR-181b expression;
furthermore, upregulated miR-181b can increase p-STAT3 levels,
resulting in the formation of a feedback loop that leads to
anti-apoptotic effects and the formation of cell colonies (71). In addition, the interaction of
miR-181b-1, cylindromatosis and STAT3 can establish a link between
inflammation and tumor formation (79). By analogy, miR-19b-3p can inhibit
mitogen-activated protein kinase kinase 3 (MAP2K3) that can bind to
STAT3 and facilitate its degradation. STAT3 is a transcription
driver of miR-19b-3p and the three components form a positive
circuit to induce ESCC progression (72). Furthermore, miR-19b-3p targeting
phosphatase and tensin homolog can induce the occurrence of ESCA
(80), which is of great
significance for miR biomarker studies performed in ECA (81).
Cisplatin is a conventional first-line
chemotherapeutic drug used for the treatment of ESCA and resistance
to this drug limits its clinical application (82). Tumor cells treated with cisplatin
can release IL-6 and induce the phosphorylation of STAT3 in ESCA.
The release of IL-6 can evoke the survival of the IL-6/STAT3
signaling pathway, finally protecting cancer cells from cisplatin.
Low expression of Let-7 is associated with low chemotherapy
sensitivity. In contrast to these observations, upregulation of
Let-7 can decrease p-STAT3 levels to counteract the activation of
the IL-6/STAT3 pathway by cisplatin and reduce the resistance to
this drug (83). The cisplatin
resistance mechanism of miR-125a-5p is similar to that of Let-7,
which is in parallel to the deactivation of the STAT3 signaling
pathway. The ability of miR-125a-5p to regulate EMT is also
relevant to the chemical sensitivity of cisplatin. By contrast,
STAT3 activated by miR-21 can increase the production of monocytic
myeloid-derived suppressor cells, which can protect tumor cells
against the effects of cisplatin. MiR-21 can increase cisplatin
resistance via the STAT3 signaling pathway in ESCC (84) (Table
I, Fig. 2).
MiR-34a mediates the miR-34a/STAT3/IL-6R feedback
loop. PD-L1 and IL-6R are downstream targets of miR-34a present in
ESCA cells. MiR-34a can inhibit them via binding to PD-L1 and
IL-6R, while IL-6R can promote STAT3 expression, which can inhibit
miR-34a. Based on the aforementioned mechanism, PD-L1 can
participate in the miR-34a/IL-6R/STAT3 feedback loop. Furthermore,
low levels of PD-L1 expression can boost the immune system. When
miR-34a levels are reduced, loss of PD-L1 expression causes an
upstream gene constraint, further promoting immune escape. As
miR-34a levels are upregulated, PD-L1 expression is restricted by
upstream molecular pathways to reverse tumor immune escape and
strengthen T-cell immune response (52,85)
(Table I; Fig. 2).
It has been shown that downregulation of the
expression levels of CPBE3 and MAP2K3 is linked to low clinical
survival and poor prognosis in ESCA, whereas miR-106b-5p and
miR-19b-3p respectively inhibit their expression levels (70,72).
It has been suggested that certain miRNAs are associated via STAT3
signaling with low survival in patients. MiR-21, which can promote
cisplatin resistance, originates from cancer-associated fibroblasts
(CAFs). The highly infiltrated CAFs are associated with a low
survival rate and can increase miR-21; therefore, overexpressed
miR-21 levels affect patient survival in ESCC (84). A reduction in the expression levels
of miR-125a-5p and miR-874-3p is often associated with a lower rate
of survival and their expression levels can also aid the
determination of the clinical stage of ESCC (43,45).
Upregulation of Let-7 expression frequently suggests improved
prognosis for patients with this disease (83) (Table
I).
ESCA is a familiar malignant tumor with a low early
diagnostic rate and late cure rate. It is necessary to positively
explore the pathogenic mechanism for formulating novel treatment
strategies. It has been found that the STAT3 signaling pathway
involving miRNAs can play a crucial role in the occurrence and
development of ESCA. Upregulation of miR-124, miR-125a-5p,
miR-296-5p, miR-874-3p, miR-17-5p, miR-149-5p, miR-30b,
miR-181c-5p, miR-494, miR-495-3p and miR-34a can form signaling
regulatory axes with STAT3 to inhibit proliferation, invasiveness
and metastasis and promote apoptosis in ESCA. However, miR-126,
miR-4286, miR-106b-5p, miR-181b and miR-19b-3p positively regulate
ESCA growth and foster malignant behaviors by interacting with
STAT3. These roles of the miRNA/STAT3 signaling axis may provide
novel opportunities for the use of miRNAs as molecular targets for
treating ESCA. Perhaps targeted promotion or inhibition of the
aforementioned miRNAs via various means can be used as a method to
treat ESCA. The STAT3 signaling pathways mediated by Let-7 and
miR-21 can influence ESCA resistance to cisplatin and further
affect drug efficacy. Increasing Let-7 levels or downregulating
miR-21 levels can promote the potential of drug therapy for ESCA.
It is worth noting that certain signaling pathways can regulate
multiple functions. MiR-125a-5p inhibits the progression of tumors
and lowers resistance to cisplatin; miR-34a not only hinders cancer
development but also increases immunity, weakening the escape of
cancer cells. The higher survival rate and improved prognosis of
patients are associated with increased expression levels of
miR-125a-5p, miR-874-3p and Let-7, while overexpression of
miR-19b-3p, miR-106b-5p and miR-21 are related to poor prognosis
and a lower survival rate. Of note, when miR-126 targets VEGF-A,
IRS-1, GOLPH3 or CDK6 and mediates the PI3K/AKT or ADAM-9/EGFR/AKT
signaling axis, it has an inhibitory effect on ESCA. As it combines
with STAT3, its effect is inverse. The same signaling molecules
have completely opposite effects on different signaling pathways.
Therefore, it is important to accurately determine the role of each
signaling pathway.
In conclusion, the complex signaling network formed
by miRNAs and STAT3 affects multiple pathophysiological processes
in ESCA. Therefore, further research is required to assess the
detailed mechanisms by which miRNAs and STAT3 signaling pathways
control ESCA. These results can provide new insights into the
clinical treatment required for various diseases and improve
patient quality of life.
Not applicable.
This work was financially supported by Sichuan Science and
Technology Program (grant no. 2022YFS0636) and Luzhou Science and
Technology Program (grant no. 2024JYJ061).
Not applicable.
XY made major contributions to the data analysis and
manuscript writing. LYF collected data and figures. YZH and HCG
participated in writing and revising the manuscript. All authors
discussed, carefully read and approved the final manuscript. Data
authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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