Sage Journals: Discover world-class research

Abstract

MicroRNAs are non-coding RNAs that regulate gene expression by targeting messenger RNA molecules in 3′ untranslated region. Mounting evidence indicates that microRNAs regulate several factors to influence various biological activities that are related to carcinogenesis, including signal transducer and activator of transcription 3, which is a transcription factor that also acts as an oncogene. MicroRNAs influence signal transducer and activator of transcription 3 either by directly targeting or via other pathway components upstream or downstream of signal transducer and activator of transcription 3 such as Janus kinases, members of the suppressor of cytokine signaling family, and other genes that regulate cell proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition. However, signal transducer and activator of transcription 3 activation changes the pattern of expression of microRNAs and mediates tumorigenesis. Moreover, the relationship between signal transducer and activator of transcription 3 and microRNAs varies among different kinds of cancers. A specific microRNA may act as an oncogene or tumor suppressor in different cancers, and microRNAs also directly or indirectly regulate signal transducer and activator of transcription 3 via pathways in the same cancers. In this review, we focus on the reciprocal regulation and roles of microRNAs and signal transducer and activator of transcription 3 in cancer, as well as describe current research progress on this relationship. A better understanding of this relationship may facilitate in the identification of targets for clinical therapeutics.

Keywords

MicroRNAs signal transducer and activator of transcription 3 signaling pathway cancer Janus kinases suppressor of cytokine signaling

Introduction

MicroRNAs (miRNAs, miRs) were first described by Victor Ambros in a research investigation on Caenorhabditis elegans genes.¹ MiRs are endogenous non-coding RNAs of 21–23 nucleotides in length that are transcribed by RNA polymerase II into pri-pre-miRNA. After a series of enzyme digestions, miRs and RNA-induced silencing complex (RICS) are combined in the 3′ untranslated region (3′-UTR) of the target gene. MiRs then promote messenger RNA (mRNA) degradation and/or inhibit mRNA translation of proteins that are involved in various biological processes, which include cell proliferation, cell cycle, apoptosis, differentiation, invasion, and metastasis.² For example, miR-124 promotes cell apoptosis and inhibits cell proliferation, invasion in non–small cell lung cancer (NSCLC), colorectal cancer, and other kinds of cancers by targeting signal transducer and activator of transcription 3 (STAT3),^3,4 MiR-203 directly targets suppressor of cytokine signaling 3 (SOCS3) and regulates cellular proliferation in breast cancer.⁵ Therefore, microRNAs are considered as key regulators of gene expression. Recent studies have shown that miRs play an important role in the pathogenesis of cancer by acting as either tumor suppressors or oncogenes. Varol et al. have indicated that the relationship between miRs and cancers is complicated. Some transcription factors could lead to the activation of various miRs; furthermore, amplifications, deletions, and translocations may also alter miR expression patterns. Polymorphisms involving cancer-related genes may influence miR biogenesis, miR target sites, and mature miR sequences.⁶ Thus, the mechanism of miRs in regulating target genes is crucial to understanding cancer progression.

STATs pertain to a family of transcription factors that were first observed in interferon (IFN) responses.⁷ STAT3 is a crucial member of the STAT protein family (which include STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) that is activated during inflammation and in cancer.⁸ STAT3 is activated by phosphorylation and cytoplasmic-to-nuclear shuttling.⁹ A previous report has shown that tyrosine phosphorylation of STAT3 contributes to oncogenesis by Src.¹⁰ Subsequent cell and animal experiments have confirmed that constitutive STAT3 activation mediates malignant transformation of cancer.^11,12 Janus kinase (JAK) is an upstream component that regulates the biological activity of STAT3.⁸ Interleukin 6 (IL6) is an inflammatory cytokine that also has biological functions in cancers and binds to the IL6 receptor (IL6R). Members of the JAK family are phosphorylated after the IL6/IL6R complexes with gp130.¹³ Members of the SOCS family (CIS, SOCS1-7) are key negative regulators of the JAK/STAT signaling pathway that acts by combining with JAK catalytic sites.^14,15 The protein inhibitor of activated STAT3 (PIAS3) blocks the DNA-binding activity of STAT3, which in turn inhibits the activation of STAT3, thereby indicating that PIAS3 is a specific inhibitor of STAT3.¹⁶

Recent studies have demonstrated that miRs and STAT3 regulate each other in various ways. In this review, we discuss the findings of recent studies on the relationship between miRs and STAT3 in cancer. We concentrate on the negative and positive regulation of miRs and STAT3 signaling pathway via direct and indirect regulatory mechanisms. Therefore, we will discuss how miRs participate in the STAT3 signaling pathway, which in turn may be potentially utilized as targets in cancer therapy.

MiRs and STAT3

MiRs directly target STAT3

Previous studies have established that miRs act as tumor suppressors by directly targeting and repressing STAT3 expression that in turn inhibits cell proliferation, invasion, migration, metastasis, epithelial–mesenchymal transition (EMT), and angiogenesis, as well as promotes cell apoptosis (Figure 1 and Table 1). MiR-148a, -9600, -124, and -320a are downregulated in lung cancer.^3,17–19 MiR-17-5p, -29b, -106a/b, -15a, -16, -17, -221, -519d, -124, and -544 are downregulated in breast cancer.^20–26 MiR-29b, -125a, and let-7a are downregulated in cervical cancer.^27–30 MiR-125b is downregulated in metastatic melanoma.³¹ MiR-519a and -124 are downregulated in glioma.^32,33 MiR-874 and -124 are downregulated in colorectal and gastric cancers.^4,34–36 MiR-143 and -124 are downregulated in esophageal carcinoma.^37,38 Let-7a is downregulated in hepatocellular carcinoma (HCC).³⁹ MiR-1181 and -130b are downregulated in pancreatic cancer.^40–42 MiR-129-5p is downregulated in laryngeal cancer.⁴³ MiR-1299 is downregulated in colon cancer.⁴⁴

Figure 1.

Regulation of miRs in the IL6/JAK/STAT3 signaling pathway. MiRs activate this signaling pathway at multiple levels by targeting SOCS and PIAS3. MiRs directly target STAT3 or indirectly target JAKs to repress the IL6/JAK/STAT3 signaling pathway.

Table 1.

MiRs that directly target STAT3.

MiR	Tissue/cell type	Target processes	References
MiR-148a	NSCLC	Proliferation, invasion	17
MiR-17-5p	Breast cancer	Apoptosis	20
MiR-29b	Cervical cancer, breast cancer	Invasion, proliferation, apoptosis, EMT, angiogenesis	21,28
MiR-125a	Cervical cancer	Apoptosis, invasion, metastasis, EMT	30
MiR-125b	Metastatic melanoma	Migration, metastasis	31
MiR-9600	NSCLC	Migration, invasion, apoptosis	18
MiR-106a/b	Breast cancer	Attenuates breast cancer stem-like cell properties	22
MiR-519a	Glioma	Proliferation, apoptosis, migration, invasion	32
MiR-874	Colorectal cancer, gastric cancer	Angiogenesis, proliferation, migration, invasion, apoptosis	34,35
MiR-143	Esophageal squamous cell carcinoma	Proliferation, migration, invasion, EMT	37
MiR-15a	Breast cancer	Proliferation, angiogenesis	23
MiR-16	Breast cancer	Proliferation, angiogenesis	23
MiR-17	Breast cancer	Proliferation, angiogenesis	23
MiR-221	Breast cancer	Proliferation, angiogenesis	23
MiR-519d	Breast cancer	Apoptosis, migration,	24
Let-7a	Cervical cancer, HCC	Proliferation, apoptosis, invasion	27,29,39
MiR-124	Esophageal cancer, NSCLC, colorectal cancer, glioma, breast cancer, gastric cancer	Apoptosis, proliferation, invasion	3,4,26,33,36,38
MiR-1181	Pancreatic cancer	Proliferation, invasion	40,41
MiR-130b	Pancreatic cancer	Proliferation, apoptosis, invasion	42
MiR-320a	Lung adenocarcinoma	Proliferation, apoptosis, migration	19
MiR-544	Breast cancer	Migration, proliferation, invasion, EMT, apoptosis	25
MiR-129-5p	Laryngeal cancer	Proliferation, invasion, migration	43
MiR-1299	Colon cancer	Proliferation, apoptosis	44

MiR: microRNA; STAT: signal transducer and activator of transcription; NSCLC: non–small cell lung cancer; EMT: epithelial–mesenchymal transition; HCC: hepatocellular carcinoma.

Therefore, directly targeting STAT3 using miRs fundamentally influences various signal transduction pathways and biological activities, which in turn may be potentially utilized as therapeutic targets.

MiRs target other components of the JAK/STAT signaling pathway

In addition to directly targeting STAT3, miRs also target other components of the JAK/STAT signaling pathway by indirectly targeting IL6/6R, JAKs, SOCS, and PIAS3, which mediates STAT3 expression (Figure 1 and Table 2).

Table 2.

MiRs target other components in JAK/STAT signaling pathway.

MiR	Target	Effect	Type of cancer	Target processes	References
MiR-340	JAK1	Tumor suppressor	HCC	Proliferation, invasion	45
MiR-204	JAK2	Tumor suppressor	Breast cancer	Apoptosis	46
MiR-216a	JAK2	Tumor suppressor	Pancreatic cancer	Apoptosis, tumor growth	47
MiR-375	JAK2	Tumor suppressor	Gastric cancer	Proliferation, migration, apoptosis	48
MiR-145	JAK2	Tumor suppressor	Bladder cancer	Metastasis	49
MiR-155-5p	SOCS1	Oncogene	Breast cancer, OSCC	Aerobic glycolysis, EMT, metastasis	52,53
MiR-222-3p	SOCS3	Oncogene	Epithelial ovarian cancer	Metastasis	60
MiR-4308	SOCS3	Oncogene	Gastric cancer	Metastasis	59
MiR-19a	SOCS1	Oncogene	NSCLC	invasion, migration	54
MiR-221	SOCS3	Oncogene	Prostate cancer	Proliferation, apoptosis, invasion	61
MiR-30d	SOCS1	Oncogene	Prostate cancer	Proliferation, invasion	56
MiR-155	SOCS1	Oncogene	Breast cancer, pancreatic cancer	Proliferation, invasion, migration	55,57
MiR-203	SOCS3	Oncogene	Breast cancer	Proliferation	5
MiR-30	SOCS3	Oncogene	Glioma	Tumorigenesis	62
MiR-194	SOCS2	Oncogene	Prostate cancer	Migration, invasion, proliferation	58
MiR-125b	IL6R	Tumor suppressor	Cholangiocarcinoma	Migration, invasion, Proliferation. apoptosis	50
Let-7c	IL6R	Tumor suppressor	Cholangiocarcinoma	Migration, invasion, proliferation, apoptosis	50
MiR-9	IL6	Tumor suppressor	Cervical cancer	Proliferation	51
MiR-18a	PIAS3	Oncogene	Gastric adenocarcinoma	Apoptosis, proliferation	63

MiR: microRNA; JAK: Janus kinase; STAT: signal transducer and activator of transcription; HCC: hepatocellular carcinoma; OSCC: oral squamous cell carcinoma; EMT: epithelial–mesenchymal transition; NSCLC: non–small cell lung cancer.

MiRs target members of the JAK family to suppress the phosphorylation of JAKs, which in turn, as a tumor suppressor, downregulates the expression of STAT3. MiR-340 suppresses cell proliferation and invasion by targeting JAK1 directly as a tumor suppressor in HCC.⁴⁵ MiR-204, -216a, and 375 suppress the JAK2/STAT3 signaling pathway by targeting JAK2 in breast, pancreatic, gastric cancer, and bladder cancer.^46–49 MiR-125b and let-7c inhibit migration, invasion, proliferation, and apoptosis in cholangiocarcinoma (CCA) by targeting IL6R.⁵⁰ MiR-9 targets IL6 to indirectly suppress STAT3 in cervical cancer.⁵¹

Conversely, JAK/STAT signaling is active when miRs target SOCS proteins, which in turn activates STAT3. MiR-155-5p, -19a, -30d, and -155 upregulate STAT3 by targeting SOCS1 in breast cancer, oral squamous cell carcinoma (OSCC), NSCLC, prostate, and pancreatic cancer.^52–57 MiR-194 acts as an oncogene by targeting SOCS2 in prostate cancer.⁵⁸ MiR-222-3p, -4308, -221, -203, -322-3p, and -30 activate STAT3 by targeting SOCS3 in different cancers (Table 1).^5,59–62 PIAS3, as a protein inhibitor of active STAT3, targets miR-18a to suppress STAT3 in gastric adenocarcinoma.⁶³

In summary, miRs regulate STAT3 by directly targeting its classic signaling pathway to inhibit or promote the expression of STAT3-interacting proteins, which reveals that the regulatory mechanism involves a complex network of interactions.

MiRs target other signaling pathway components

Other miRs indirectly regulate STAT3 by targeting components of other pathways (Figure 2 and Table 3). For example, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored glycoprotein that acts as a repressive factor of matrix metalloproteinase 9 (MMP-9) and MMP-2; miR-590-5p is upregulated in gastric cancer and contributes to cell growth and invasion. MiR-590-5p regulates STAT3 by binding to the 3′-UTR of RECK, as well as promotes cell invasion in gastric cancer. Therefore, as an oncogene, the miR-590-5p/RECK axis is an important pathway that regulates the expression of STAT3 in gastric cancer.⁶⁴ MiR-126 is downregulated in osteosarcoma, and the overexpression of miR-126 inhibits cell proliferation, migration, invasion, and EMT, thereby demonstrating that miR-126 functions as a tumor suppressor. Zinc finger E-box binding homeobox 1 (ZEB1) has been verified as a target gene of miR-126, and silencing ZEB1 results in the inactivation of the JAK1/STAT3 pathway. Thus, the miR-126/ZEB1 signaling pathway also influences STAT3 activation.⁶⁵ In conclusion, miR-590-5p, -424, and -221/222 indirectly activate STAT3 by targeting RECK, COP1, ADIPOR1, and PDLIM2 individually to promote cell proliferation, invasion, and EMT.^64,66–68 MiR-24-3p, -1207-5p, -363, -203, -197, -199a-3p, -30c, -519d, -27b-3p, -99a, -101, -302b, -12b, and -34a have been reported to target FGF11, CSF1, S1PR1, LIFR, CKS1B, C-Met, TWF1, RhoC, ROR1 IGF1R, CXCR7, RUNX1, ZEB1, and INH3, respectively, as tumor suppressors in various cancers.^{28,50,69–79}

Figure 2.

STAT3 regulation by miRs via other signaling pathway components. Other pathways by which miRs directly or indirectly regulate STAT3 expression.

Table 3.

MiRs target the components of other signaling pathways.

MiR	Target	Effect	Type of cancer	Target processes	References
MiR-590-5p	RECK	Oncogene	Gastric cancer	Proliferation, invasion	64
MiR-24-3p	FGF11	Tumor suppressor	Nasopharyngeal carcinoma	Proliferation	69
MiR-1207-5p	CSF1	Tumor suppressor	Lung cancer	EMT, proliferation, migration, invasion	70
MiR-203	LIFR	Tumor suppressor	Rhabdomyosarcoma	Proliferation	71
MiR-197	CKS1B	Tumor Suppressor	NSCLC	Metastasis, apoptosis, chemoresistance	72
MiR-363	S1PR1	Tumor suppressor	HCC	Proliferation, apoptosis	73
MiR-199a-3p	C-Met	Tumor Suppressor	RCC	Proliferation	74
MiR-221/-222	ADIPOR1	Oncogene	Breast cancer	EMT, invasion	68
MiR-30c	TWF1	Tumor suppressor	Breast cancer	Invasion, metastasis	75
MiR-519d	Rhoc	Tumor suppressor	Ovarian carcinoma	Apoptosis, invasion	76
MiR-424	COP1	Oncogene	Prostate cancer	EMT	66
MiR-27b-3p	ROR1	Tumor suppressor	Gastric cancer	Proliferation	77
MiR-99a	IGF1R	Tumor suppressor	Cholangiocarcinoma	Migration, invasion, proliferation, apoptosis	50
MiR-101	CXCR7	Tumor suppressor	Breast cancer	Proliferation, invasion, metastasis	78
MiR-302b	RUNX1	Tumor suppressor	Epithelial ovarian cancer	Proliferation, apoptosis	79
MiR-221/-222	PDLIM2	Oncogene	Colorectal cancer	Proliferation	67
MiR-126	ZEB1	Tumor suppressor	Osteosarcoma	Proliferation, EMT, migration, invasion	65
MiR-34a	INH3	Tumor suppressor	Cancer cancer	EMT, metastasis	28

MiR: microRNA; EMT: epithelial–mesenchymal transition; NSCLC: non–small cell lung cancer; HCC: hepatocellular carcinoma; RCC: renal cell carcinoma.

All the additional examples of miRs that regulate STAT3 via a non-classical pathway are listed in Table 3 and Figure 2. These non-classical pathways create numerous nodes in the cellular regulatory network; therefore, miRs regulate STAT3 by targeting proteins with different functions. These proteins, acting as either oncogenes or tumor suppressors, modulate STAT3 expression; however, details on the underlying regulatory mechanism remain unclear.

MiRs regulate STAT3 using an unidentified target locus

Previous reports have shown that MiRs regulate STAT3 expression; however, the underlying mechanism remains unclear. For example, STAT3 is an oncogene that promotes cell proliferation and migration. Yu et al. showed that miR-148a expression effectively downregulates STAT3 activation; however, its underlying mechanism remains unclear. STAT3 is a downstream factor of miR-148a and not a target locus. There is currently a need to identify the target locus of miR-148a and the relationship between 148a and STAT3 in gastric cancer.⁸⁰ All miRs that influence STAT3 expression in different kinds of cancers act as upstream factors (Figure 3 and Table 4). MiR-199a5p, -205, -373, and -139-5p act as oncogenes that upregulate STAT3 in osteosarcoma and colorectal carcinoma.^81–83 On the contrary, miR-148a, -491-5p, -31, -146a, -375, -204, -197, -133b, and -135a inhibit STAT3 expression in gastric cancer, pancreatic cancer, cervical cancer, colorectal cancer, cutaneous squamous cell carcinoma, HCC, and renal carcinoma.^80,84–90

Figure 3.

STAT3 regulation by miRs with unidentified target loci. MiRs regulate STAT3 via an unknown mechanism and unidentified target loci.

Table 4.

MiRs that regulate STAT3 with unidentified target loci.

MiR	Effect	Type of cancer	MiR function	References
MiR-199a-5p	Oncogene	Osteosarcoma	Proliferation	81
MiR-148a	Tumor suppressor	Gastric cancer	Proliferation, migration	80
MiR-205	Oncogene	Colorectal carcinoma	Cell differentiation	82
MiR-373	Oncogene	Colorectal carcinoma	Invasion	82
MiR-139-5p	Oncogene	Colorectal carcinoma	Proliferation, apoptosis	83
MiR-491-5p	Tumor suppressor	Pancreatic cancer	Proliferation, apoptosis	84
MiR-31	Tumor suppressor	Gastric cancer	Proliferation, apoptosis	85
MiR-146a	Tumor suppressor	Cervical cancer, colorectal cancer	Proliferation, migration, invasion	87
MiR-375	Tumor suppressor	Colorectal cancer	Proliferation, migration	86
MiR-204	Tumor suppressor	Cutaneous squamous cell carcinoma	Proliferation	88
MiR-197	Tumor suppressor	Hepatocellular carcinoma	Proliferation, invasion, apoptosis	89
MiR-133b	Tumor suppressor	Renal carcinoma	Proliferation, apoptosis	90
MiR-135a	Tumor suppressor	Renal carcinoma	Proliferation, apoptosis	90

MiR: microRNA; STAT3: signal transducer and activator of transcription 3.

In summary, the regulatory function of miRs and STAT3 is unclear, and no target locus in specific signaling pathway has been identified. However, previous studies have shown that STAT3 is involved in the regulatory network of cancer progression.

STAT3 upregulate or downregulate MiRs

Previous studies have shown that miRs regulate STAT3 and STAT3-related signaling pathways. Similarly, STAT3 also modulates the expression of miRs, which in turn regulates cell proliferation, migration, apoptosis, invasion, and EMT in various cancers (Figure 3 and Table 5).

Table 5.

STAT3-mediated regulation of miRs.

MiR	Type of cancer	Change in expression	Subsequent reaction	References
MiR-23a	HCC	Upregulated	Decrease glucose production	91
MiR-181b	Colorectal cancer	Upregulated	Proliferation, migration, apoptosis	53
MiR-34a	Colorectal cancer, breast cancer	Downregulated	EMT, metastasis, invasion	92–94
MiR-200	Breast cancer	Upregulated	EMT, invasion	95
Let-7b/d/e/g	Breast cancer	Upregulated	EMT, invasion	95
MiR-106a	Ovarian cancer	Upregulated	Proliferation, invasion, migration, EMT	97
MiR-182-5p	Glioma	Upregulated	Proliferation, invasion, migration	98
MiR-181a	Breast cancer	Upregulated	Apoptosis, metastasis	96
MiR-383	Epidermal carcinoma	Downregulated	Apoptosis	99
MiR-92a	Lung cancer	Upregulated	Invasion, migration	101
MiR-520d-5p	Gastric cancer	Downregulated	Proliferation, apoptosis	100

STAT3: signal transducer and activator of transcription 3; miR: microRNA; HCC: hepatocellular carcinoma; EMT: epithelial–mesenchymal transition.

Wang et al. used a mouse model and conducted cell experiments to prove that the expression of miR-23a is upregulated in HCC mice. Furthermore, they showed that STAT3 upregulates miR-23a, which targets G6PC, and thus the activation of the STAT3/miR-23a pathway could lead to a decrease in glucose production.⁹¹ In colorectal cancer, STAT3 upregulates miR-181b, which in turn promotes cell proliferation and migration, as well as inhibits cell apoptosis.⁵³ Conversely, STAT3 downregulates miR-34a in colorectal^92,93 and breast cancer.⁹⁴ Moreover, STAT3 also promotes the expression of other miRs such as miR-200 and -181a in breast cancer.^95,96 Members of the Let-7 family such as let-7a and-7c play an important role in cancer.^27,29,39,50 Furthermore, STAT3-coordinated let-7b/d/e/g induces invasion and EMT in breast cancer.⁹⁵ In ovarian cancer, the IL6-mediated activation of STAT3 upregulates miR-106a, which promotes invasion, migration, proliferation, and EMT via the IL6/STAT3 signaling pathway.⁹⁷ MiR-182-5p acts as an oncogene in glioma, targeting PCDH8, which is also activated by STAT3.⁹⁸ STAT3 is downregulated by miR-383 and -520d-5p in epidermal carcinoma and gastric cancer, respectively.^99,100 In lung cancer, STAT3 upregulates miR-92a to target RECK and downregulates RECK, which in turn promote invasion and migration.¹⁰¹

The cross talk between miRs in regulating STAT3 activity

Collectively, we have summarized the current reports on the relationship between miRs and STAT3 in various types of cancers. The role of miRs in tumorigenesis is supported by a variety of scientific findings. We have enumerated the interactions between miRs and the STAT3 signaling pathway below. In addition to directly targeting STAT3, miRs also interact with other genes in the IL6/JAK/STAT3 pathway and other components upstream of STAT3. Furthermore, by acting as STAT3 downstream effectors, miRs are also up/downregulated by STAT3 activation.

A specific miR may play the same function in different cancers. For example, miR-375, by acting as a tumor suppressor, targets JAK2 in gastric cancer. Gain- and loss-of-function experiments have determined that miR-375 mediates JAK2/STAT3 activation, which in turn could be potentially utilized as a novel clinical therapeutic target for gastric cancer.⁴⁸ However, another study showed that a JAK2/STAT3-related signaling pathway is downregulated in miR-375-overexpressing cells, and cell proliferation is inhibited in colorectal cancer, thereby indicating that miR-375 acts as a tumor suppressor, preventing the occurrence and development of colorectal cancer, although its target locus remains unclear.⁸⁶ Nevertheless, miR-375 targets JAK2 in cancer, thereby downregulating STAT3 and inhibiting tumorigenesis. MiR-148a, -204, and -197 play a similar function in cancer as that of miR-375.^{17,46,72,80,88,89} These studies indicate that miRs play a central role in various cancers, that is, as oncogene or tumor suppressor, although the interrelationship between these miR- and STAT3-related signaling pathways remains unclear.

Another phenomenon involving the relationship between miR family and STAT3 is that different miRs belonging to the same miR family also play the same function in cancers. For example, in the miR-125 family, whose members act as tumor suppressors, miR-125a directly targets STAT3 in cervical cancer, and its overexpression suppresses cell growth, invasion, and EMT, as well as regulates cell cycle by inhibiting G2/M checkpoint proteins,³⁰ focal adhesion kinase (FAK) is a protein tyrosine kinase that promotes cell migration, invasion, and adhesion via STAT3 activation. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis indicated that miR-125b is upregulated in siFAK cells compared to siNC cells, suggesting that miR-125b participates in the FAK/STAT3 signaling pathway and demonstrating that miR-125b directly targets the 3′-UTR of STAT3 in melanoma via the promotion of FAK.³¹ MiR-125b indirectly inhibits STAT3 by targeting IL6R in CCA, thereby resulting in the inhibition of cell proliferation, migration, and invasion and promotion of cell apoptosis via the miR-125b/IL6R/STAT3 pathway.⁵⁰ Members of this miR family include miR-181, -17, -519, -155, and -30, which show a similar function as that of miR-125.^{20,23,24,32,52,53,55–57,62,75,76,96} Members of the same miR family regulate the expression of specific proteins that influence cancer progression, thereby suggesting that these may be potentially utilized as novel therapeutic targets in cancer treatment regimens.

SOCS3, which is the most common negative regulator of STAT3 in the SOCS family, indirectly downregulates STAT3 activity in breast cancer by targeting miR-203. MiR-203, which acts as an oncogene, inhibits the SOCS3/STAT3 pathway, thereby preventing breast carcinogenesis.⁵ However, miR-203 also acts as a tumor suppressor that targets leukemia inhibitory factor receptor (LIFR) in rhabdomyosarcoma (RMS), thereby negatively regulating the STAT3 pathway, inhibiting myogenic differentiation and decreasing the proliferation and migration in RMS.⁷¹ Therefore, these studies thus demonstrate that a specific miR may play opposite functions in different cancers, which in turn may be potentially utilized as a novel target in cancer therapeutics. Further investigations on the function of miRs may provide insights into the clinical targeted therapy in different cancers.

Comparison between miRs and pharmacological inhibitors in regulating STAT3 negatively

STAT3 has been localized to the cytoplasm, is activated by phosphorylation, and plays a role in tumorigenesis, thereby rendering itself an ideal target for cancer therapeutics. Recent reviews have described the use of pharmacological inhibitors in targeting STAT3 via five major routes, which include its DNA-binding domain, N-terminal domain, SH2 domain, its interaction with importin, and upstream kinase activity.¹⁰² Clinical trials have investigated the use of pharmacological inhibitors such as butein, capsaicin, and other macromolecules of similar activity such as anti-cancer therapeutic agents.^102,103

mRNA serves as the template in DNA transcription that results in the synthesis of proteins. MiRs and RICS have been utilized to target the 3′-UTR of mRNAs to inhibit protein translation. However, the main mechanism of pharmacological inhibitors involves blocking the DNA-binding domain of STAT3 or repressing other components of the STAT3 signaling pathway such as JAKs. Therefore, compared to pharmacological inhibitors, miRs negatively regulate STAT3 with a higher degree of specificity and may thus serve as a novel approach for targeted gene therapy.

Conclusion

Collectively, we have summarized the current reports on the relationship between miRs and the STAT3 signaling pathway in different kinds of cancers. This signaling pathway modulates cell proliferation, migration, metastasis, EMT, cell cycle, and apoptosis, and various miRs regulate STAT3 activity. This review provides insights into novel schemes for clinical therapeutics of cancer.

Footnotes

Acknowledgements

J.Z. contributed to the conception of the study. J.L., Q.W., G.M., X.L., H.Z., and W.L. contributed significantly to the analysis and manuscript preparation; L.Z. performed the data analyses and wrote the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Lee

Feinbaum

Ambros

. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843–854.

Gurtan

Sharp

. The role of miRNAs in regulating gene expression networks. J Mol Biol 2013; 425: 3582–3600.

. The tumor suppressor miR-124 inhibits cell proliferation by targeting STAT3 and functions as a prognostic marker for postoperative NSCLC patients. Int J Oncol 2015; 46: 798–808.

Zhang

Yue

. MiR-124 suppresses growth of human colorectal cancer by inhibiting STAT3. PLoS ONE 2013; 8: e70300.

Muhammad

Bhattacharya

Steele

. Anti-miR-203 suppresses ER-positive breast cancer growth and stemness by targeting SOCS3. Oncotarget 2016; 7: 58595–58605.

Varol

Konac

Gurocak

. The realm of microRNAs in cancers. Mol Biol Rep 2011; 38: 1079–1089.

Darnell

Jr Kerr

Stark

. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415–1421.

Rawlings

Rosler

Harrison

. The JAK/STAT signaling pathway. J Cell Sci 2004; 117: 1281–1283.

Greenhill

Rose-John

Lissilaa

. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol 2011; 186: 1199–1208.

10.

Meyer

Campbell

. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 1995; 269: 81–83.

11.

Bromberg

Wrzeszczynska

Devgan

. Stat3 as an oncogene. Cell 1999; 98: 295–303.

12.

Schlessinger

Levy

. Malignant transformation but not normal cell growth depends on signal transducer and activator of transcription 3. Cancer Res 2005; 65: 5828–5834.

13.

Yang

Liao

Agarwal

. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 2007; 21: 1396–1408.

14.

Lee

Kim

Sethi

. Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel. Oncotarget 2015; 6: 6386–6405.

15.

Zhang

Zhou

Zhang

. Amyloid-beta induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway. Diabetes 2012; 61: 1434–1443.

16.

Chung

Liao

Liu

. Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997; 278: 1803–1805.

17.

Xue

. MicroRNA-148a suppresses proliferation and invasion potential of non-small cell lung carcinomas via regulation of STAT3. OncoTargets Ther 2017; 10: 1353–1361.

18.

Sun

C-C

S-J

Zhang

. The novel miR-9600 suppresses tumor progression and promotes paclitaxel sensitivity in non–small-cell lung cancer through altering STAT3 expression. Mol Ther Nucleic Acids 2016; 5: e387.

19.

. MiR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals. Cancer Biol Ther 2017; 18: 142–151.

20.

Liao

Xiang

. STAT3 is required for MiR-17-5p-mediated sensitization to chemotherapy-induced apoptosis in breast cancer cells. Oncotarget 2017; 8: 15763–15774.

21.

Qin

Zhang

. Special suppressive role of miR-29b in HER2-positive breast cancer cells by targeting Stat3. Am J Transl Res 2015; 7: 878–890.

22.

Liu

Zhang

Sun

. EMMPRIN down-regulating miR-106a/b modifies breast cancer stem-like cell properties via interaction with fibroblasts through STAT3 and HIF-1α. Sci Rep 2016; 6: 28329.

23.

Srinivas

Ramaiah

Lavanya

. Novel etoposide analogue modulates expression of angiogenesis associated microRNAs and regulates cell proliferation by targeting STAT3 in breast cancer. PLoS ONE 2015; 10: e0142006.

24.

Deng

Zhao

Wang

. miR-519d-mediated downregulation of STAT3 suppresses breast cancer progression. Oncol Rep 2015; 34: 2188–2194.

25.

Zhu

Wang

Zhu

. MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer. Biol Chem 2016; 397: 1087–1095.

26.

Xiong

. MicroRNA-124 enhances response to radiotherapy in human epidermal growth factor receptor 2-positive breast cancer cells by targeting signal transducer and activator of transcription 3. Croat Med J 2016; 57: 457–464.

27.

Shishodia

Shukla

Srivastava

. Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis. Mol Cancer 2015; 14: 116.

28.

Rokavec

Jiang

. Antagonistic effects of p53 and HIF1A on microRNA-34a regulation of PPP1R11 and STAT3 and hypoxia-induced epithelial to mesenchymal transition in colorectal cancer cells. Gastroenterology. Epub ahead of print 20 April 2017. DOI: 10.1053/j.gastro.2017.04.017.

29.

Shishodia

Verma

Srivastava

. Deregulation of microRNAs Let-7a and miR-21 mediate aberrant STAT3 signaling during human papillomavirus-induced cervical carcinogenesis: role of E6 oncoprotein. BMC Cancer 2014; 14: 996.

30.

Fan

Cui

. MiR-125a promotes paclitaxel sensitivity in cervical cancer through altering STAT3 expression. Oncogenesis 2016; 5: e223.

31.

Pei

Lan

Chen

. FAK regulates E-cadherin expression via p-SrcY416/p-ERK1/2/p-Stat3Y705 and PPARgamma/miR-125b/Stat3 signaling pathway in B16F10 melanoma cells. Oncotarget 2017; 8: 13898–13908.

32.

Hong

Ya-Wei

Hai

. MiR-519a functions as a tumor suppressor in glioma by targeting the oncogenic STAT3 pathway. J Neurooncol 2016; 128: 35–45.

33.

Wei

Wang

Kong

. miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 2013; 73: 3913–3926.

34.

Zhang

Tang

Zhi

. miR-874 functions as a tumor suppressor by inhibiting angiogenesis through STAT3/VEGF-A pathway in gastric cancer. Oncotarget 2015; 6: 1605–1617.

35.

Zhao

Dong

. MiR-874 inhibits cell growth and induces apoptosis by targeting STAT3 in human colorectal cancer cells. Eur Rev Med Pharmacol Sci 2016; 20: 269–277.

36.

Zheng

Xiao

Tong

. Paeoniflorin inhibits human gastric carcinoma cell proliferation through up-regulation of microRNA-124 and suppression of PI3K/Akt and STAT3 signaling. World J Gastroenterol 2015; 21: 7197–7207.

37.

Liu

Mao

Zhang

. MiR-143 inhibits tumor cell proliferation and invasion by targeting STAT3 in esophageal squamous cell carcinoma. Cancer Lett 2016; 373: 97–108.

38.

Cheng

Nian

. STAT3 is involved in miR-124-mediated suppressive effects on esophageal cancer cells. BMC Cancer 2015; 15: 306.

39.

Wang

Toh

. Lethal-7 is down-regulated by the hepatitis B virus × protein and targets signal transducer and activator of transcription 3. J Hepatol 2010; 53: 57–66.

40.

Jiang

. MiR-1181 inhibits stem cell-like phenotypes and suppresses SOX2 and STAT3 in human pancreatic cancer. Cancer Lett 2015; 356: 962–970.

41.

Wang

Guo

Ding

. miR-1181 inhibits invasion and proliferation via STAT3 in pancreatic cancer. World J Gastroenterol 2017; 23: 1594–1601.

42.

Zhao

Zhang

Shi

. MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3. PLoS ONE 2013; 8: e73803.

43.

Shen

Huang

. Upregulation of miR-129-5p affects laryngeal cancer cell proliferation, invasiveness, and migration by affecting STAT3 expression. Tumour Biol 2016; 37: 1789–1796.

44.

Wang

. MicroRNA-1299 is a negative regulator of STAT3 in colon cancer. Oncol Rep 2017; 37: 3227–3234.

45.

Yuan

Xiao

. MicroRNA-340 inhibits the proliferation and invasion of hepatocellular carcinoma cells by targeting JAK1. Biochem Biophys Res Commun 2017; 483: 578–584.

46.

Wang

Qiu

Zhang

. MicroRNA-204 targets JAK2 in breast cancer and induces cell apoptosis through the STAT3/BCl-2/survivin pathway. Int J Clin Exp Pathol 2015; 8: 5017–5025.

47.

Wang

Chen

Tang

. MicroRNA-216a inhibits pancreatic cancer by directly targeting Janus kinase 2. Oncol Rep 2014; 32: 2824–2830.

48.

Miao

Liu

Xie

. miR-375 inhibits Helicobacter pylori-induced gastric carcinogenesis by blocking JAK2-STAT3 signaling. Cancer Immunol Immunother 2014; 63: 699–711.

49.

Jiang

Huang

. Role of STAT3 and FOXO1 in the divergent therapeutic responses of non-metastatic and metastatic bladder cancer cells to miR-145. Mol Cancer Ther 2017; 16: 924–935.

50.

Lin

Han

. Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma. Oncogene 2016; 35: 3376–3386.

51.

Zhang

Jia

Zhao

. Down-regulation of microRNA-9 leads to activation of IL-6/Jak/STAT3 pathway through directly targeting IL-6 in HeLa cell. Mol Carcinogen 2016; 55: 732–742.

52.

Baba

Hasegawa

Nagai

. MicroRNA-155-5p is associated with oral squamous cell carcinoma metastasis and poor prognosis. J Oral Pathol Med 2016; 45: 248–255.

53.

Lei

Lin

. 3B, a novel photosensitizer, inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells. Biomed Pharmacother 2016; 82: 141–150.

54.

Wang

Chen

. MicroRNA-19a functions as an oncogenic microRNA in non-small cell lung cancer by targeting the suppressor of cytokine signaling 1 and mediating STAT3 activation. Int J Mol Med 2015; 35: 839–846.

55.

Huang

. Regulation of miR-155 affects pancreatic cancer cell invasiveness and migration by modulating the STAT3 signaling pathway through SOCS1. Oncol Rep 2013; 30: 1223–1230.

56.

Kobayashi

Uemura

Nagahama

. Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget 2012; 3: 1455–1471.

57.

Shen

Wang

. MiRNA-155 mediates TAM resistance by modulating SOCS6-STAT3 signalling pathway in breast cancer. Am J Transl Res 2015; 7: 2115–2126.

58.

Das

Gregory

Fernandes

. MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2. Cancer Res 2017; 77: 1021–1034.

59.

Wang

. The functional SOCS3 RS115785973 variant regulated by MiR-4308 promotes gastric cancer development in Chinese population. Cell Physiol Biochem 2016; 38: 1796–1802.

60.

Ying

. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget 2016; 7: 43076–43087.

61.

Kneitz

Krebs

Kalogirou

. Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3. Cancer Res 2014; 74: 2591–2603.

62.

Che

Sun

Wang

. miR-30 overexpression promotes glioma stem cells by regulating Jak/STAT3 signaling pathway. Tumour Biol 2015; 36: 6805–6811.

63.

Takanashi

Bodigin

. MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis. Br J Cancer 2013; 108: 653–661.

64.

Shen

Zhang

. miR-590-5p regulates gastric cancer cell growth and chemosensitivity through RECK and the AKT/ERK pathway. Onco Targets Ther 2016; 9: 6009–6019.

65.

Jiang

Zhang

Liu

. MicroRNA-126 inhibits proliferation, migration, invasion and EMT in osteosarcoma by targeting ZEB1. J Cell Biochem. Epub ahead of print 5 April 2017. DOI: 10.1002/jcb.26024.

66.

Dallavalle

Albino

Civenni

. MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression. J Clin Invest 2016; 126: 4585–4602.

67.

Liu

Sun

Wang

. A microRNA 221- and 222-mediated feedback loop maintains constitutive activation of NFkappaB and STAT3 in colorectal cancer cells. Gastroenterology 2014; 147: 847–859.e11.

68.

Hwang

Stinson

. miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS ONE 2013; 8: e66502.

69.

Zhang

Cai

. Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol 2016; 240: 329–340.

70.

Dang

Qin

Fan

. miR-1207-5p suppresses lung cancer growth and metastasis by targeting CSF1. Oncotarget 2016; 7: 32421–32432.

71.

Diao

Guo

Jiang

. miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma. J Biol Chem 2014; 289: 529–539.

72.

Fujita

Yagishita

Hagiwara

. The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther 2015; 23: 717–727.

73.

Zhou

Huang

Zhao

. MicroRNA-363-mediated downregulation of S1PR1 suppresses the proliferation of hepatocellular carcinoma cells. Cell Signal 2014; 26: 1347–1354.

74.

Huang

Dong

Zhang

. miR-199a-3p inhibits hepatocyte growth factor/c-Met signaling in renal cancer carcinoma. Tumour Biol 2014; 35: 5833–5843.

75.

Bockhorn

Yee

Chang

. MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion. Breast Cancer Res Treat 2013; 137: 373–382.

76.

Sang

Zong

Wang

. E2F-1 targets miR-519d to regulate the expression of the ras homolog gene family member C. Oncotarget 2017; 8: 14777–14793.

77.

Tao

Zhi

Zhang

. miR-27b-3p suppresses cell proliferation through targeting receptor tyrosine kinase like orphan receptor 1 in gastric cancer. J Exp Clin Cancer Res 2015; 34: 139.

78.

Jia

Liu

. MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7. Oncotarget 2015; 6: 30818–30830.

79.

Yin

Yang

. MicroRNA-302b suppresses human epithelial ovarian cancer cell growth by targeting RUNX1. Cell Physiol Biochem 2014; 34: 2209–2220.

80.

. MiR-148a functions as a tumor suppressor by targeting CCK-BR via inactivating STAT3 and Akt in human gastric cancer. PLoS ONE 2016; 11: e0158961.

81.

Wang

Guo

. MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma. Sci Rep 2017; 7: 41456.

82.

Eyking

Reis

Frank

. MiR-205 and MiR-373 are associated with aggressive human mucinous colorectal cancer. PLoS ONE 2016; 11: e0156871.

83.

Zou

Mao

Yang

. Targeted deletion of miR-139-5p activates MAPK, NF-kappaB and STAT3 signaling and promotes intestinal inflammation and colorectal cancer. FEBS J 2016; 283: 1438–1452.

84.

Guo

Wang

Shi

. MicroRNA miR-491-5p targeting both TP53 and Bcl-XL induces cell apoptosis in SW1990 pancreatic cancer cells through mitochondria mediated pathway. Molecules 2012; 17: 14733–14747.

85.

Ruoming

Zhen

Tengteng

. Tumor suppressor microRNA-31 inhibits gastric carcinogenesis by targeting Smad4 and SGPP2. Cancer Gene Ther 2015; 22: 564–572.

86.

Wei

Yang

Han

. microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways. Oncotarget 2017; 8: 16633–16641.

87.

Sathyanarayanan

Chandrasekaran

Karunagaran

. microRNA-146a inhibits proliferation, migration and invasion of human cervical and colorectal cancer cells. Biochem Biophys Res Commun 2016; 480: 528–533.

88.

Toll

Salgado

Espinet

. MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression. Mol Cancer 2016; 15: 53.

89.

Wang

Yang

. Reciprocal control of miR-197 and IL-6/STAT3 pathway reveals miR-197 as potential therapeutic target for hepatocellular carcinoma. Oncoimmunology 2015; 4: e1031440.

90.

Zhou

Gao

. miRNA-133b and miRNA-135a induce apoptosis via the JAK2/STAT3 signaling pathway in human renal carcinoma cells. Biomed Pharmacother 2016; 84: 722–729.

91.

Wang

Hsu

Frankel

. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology 2012; 56: 186–197.

92.

Rokavec

Hermeking

. Soluble IL6R represents a miR-34a target: potential implications for the recently identified IL-6R/STAT3/miR-34a feed-back loop. Oncotarget 2015; 6: 14026–14032.

93.

Rokavec

Oner

. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 2014; 124: 1853–1867.

94.

Avtanski

Nagalingam

Kuppusamy

. Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-beta-catenin signaling axis in a microRNA-34a dependent manner. Oncotarget 2015; 6: 16396–16410.

95.

Guo

Chen

Shi

. Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition. Oncogene 2013; 32: 5272–5282.

96.

Niu

Xue

Chi

. Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. Oncogene 2016; 35: 1302–1313.

97.

Chen

Zhang

Sheng

. MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells. Oncol Rep 2016; 36: 2135–2141.

98.

Xue

Zhou

. miR-182-5p induced by STAT3 activation promotes glioma tumorigenesis. Cancer Res 2016; 76: 4293–4304.

99.

Liao

Zheng

. STAT3 regulated ATR via microRNA-383 to control DNA damage to affect apoptosis in A431 cells. Cell Signal 2015; 27: 2285–2295.

100.

Guo

Zhao

. Gastric cancer cell proliferation and survival is enabled by a cyclophilin B/STAT3/miR-520d-5p signaling feedback loop. Cancer Res 2017; 77: 1227–1240.

101.

Lin

Chiang

Hung

. STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. Br J Cancer 2013; 109: 731–738.

102.

Chai

Shanmugam

Arfuso

. Targeting transcription factor STAT3 for cancer prevention and therapy. Pharmacol Ther 2016; 162: 86–97.

103.

Siveen

Sikka

Surana

. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta 2014; 1845: 136–154.

The relationship between microRNAs and the STAT3-related signaling pathway in cancer

Abstract

Keywords

Introduction

MiRs and STAT3

MiRs directly target STAT3

MiRs target other components of the JAK/STAT signaling pathway

MiRs target other signaling pathway components

MiRs regulate STAT3 using an unidentified target locus

STAT3 upregulate or downregulate MiRs

The cross talk between miRs in regulating STAT3 activity

Comparison between miRs and pharmacological inhibitors in regulating STAT3 negatively

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References