Next Article in Journal
The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers
Next Article in Special Issue
STAT3 and STAT5 Targeting for Simultaneous Management of Melanoma and Autoimmune Diseases
Previous Article in Journal
FOXO1 Confers Maintenance of the Dark Zone Proliferation and Survival Program and Can Be Pharmacologically Targeted in Burkitt Lymphoma
Previous Article in Special Issue
Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression

Cancers 2019, 11(10), 1428; https://doi.org/10.3390/cancers11101428

Review
STAT3 and STAT5 Activation in Solid Cancers
1
Department of Biochemistry and Molecular Medicine, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, QC, H3C 3J7, Canada
2
CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada
3
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna 1210, Austria
*
Author to whom correspondence should be addressed.
Received: 1 August 2019 / Accepted: 18 September 2019 / Published: 25 September 2019

Abstract

:
The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.
Keywords:
solid cancers; cell cycle; apoptosis; inflammation; mitochondria; stemness; tumor suppression

1. Introduction

Activation of Signal Transducer and Activator of Transcription (STAT) proteins has been linked to many human cancers. STATs were initially discovered as latent cytosolic transcription factors that are phosphorylated by the Janus Kinase (JAK) family upon stimulation of membrane-associated cytokine and growth factor receptors. Phosphorylation triggers STAT dimerization and translocation to the nucleus to bind specific promoters and regulate transcription [1]. Here, we review the role of STAT family members STAT3 and STAT5 in solid human malignancies, as well as the mechanisms that may explain their association with either worse or better prognosis.

2. STAT3 and STAT5 in Solid Cancers

The discovery of cancer genes has been propelled by genetic analyses and more recently by next generation DNA sequencing technologies. Combined, these studies have identified 127 significantly mutated cancer genes that cover diverse signaling pathways [2]. Mutations acting as drivers in cancer are positively selected during tumor growth and constitute solid proof of the involvement of a particular gene as a driver in the disease. Mutations in STAT3 and STAT5 have been reported in patients with solid cancers, but unlike hyperactivation of the JAK/STAT pathway, STAT3/5 mutations in cancer are relatively infrequent and occur mostly in hematological malignancies.
An overview of reported STAT3/5 mutations in solid cancers is illustrated in Figure 1, based on data collected from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Mutations in STAT3 are more prevalent than mutations in STAT5A or STAT5B genes. Noticeably, gastrointestinal cancers have the highest rates of STAT3/5 mutations compared with other solid cancers (Figure 1). Missense mutations tend to cluster within the SH2 domain, where gain-of-function mutations were previously characterized [3,4], as well as within the DNA binding domain and to an extent the N-terminal domain (Figure 1A). Interestingly, the STAT3 Tyrosine 640 into Phenylalanine (Y640F) hotspot gain-of-function mutation reported in various lymphoid malignancies has also been detected in patients with liver cancer (Figure 1A). Nonsense and frameshift mutations are less frequent and more disperse, likely representing loss-of-function events (Figure 1B). Notably, a hotspot frameshift mutation at position Q368 within the DNA binding domain of STAT5B has been reported in 24 patients with various types of carcinoma; this frameshift generates a stop codon shortly after the mutation and is therefore likely to be loss-of-function, although characterization of this mutation has not been performed.
As opposed to mutation rates, STAT3/5 activation is very frequent in human cancers, perhaps reflecting increased cytokine signaling or mutations in cytokine receptors or negative regulators. STAT3/5 activation can be detected using antibodies that measure total levels or activation marks in STAT3/5 proteins (e.g. tyrosine phosphorylation). A better assessment of STAT3/5 activation can be obtained by measuring downstream signaling targets (i.e., mRNA levels of STAT3 [5] and STAT5 [6] target genes). A recent metanalysis of 63 different studies concluded that STAT3 protein overexpression was significantly associated with a worse 3-year overall survival (OS) (OR = 2.06, 95% CI = 1.57 to 2.71, p < 0.00001) and 5-year OS (OR = 2.00, 95% CI = 1.53 to 2.63, p < 0.00001) in patients with solid tumors [7]. Elevated STAT3 expression was associated with poor prognosis in gastric cancer, lung cancer, gliomas, hepatic cancer, osteosarcoma, prostate cancer and pancreatic cancer. However, high STAT3 protein expression levels predicted a better prognosis for breast cancer [7]. This study mixed data of both STAT3 and phospho-STAT3 (p-STAT3) expression limiting its ability to associate pathway activation to prognosis. Here, we summarize the data linking activation of STAT3/5 to overall survival in several major human solid cancers identifying the biomarkers used in each study (Table 1). Taken together, the results clearly show that STAT3 and STAT5 are important cancer genes despite their relatively low mutation frequency.
STAT3 activation is clearly a factor linked to bad prognosis in patients with lung cancer, liver cancer, renal cell carcinoma (RCC) and gliomas. In other tumors, the association is not significant. In solid tumors, STAT3 activation is more frequent than STAT5 activation although no explanation for this difference was proposed. In prostate cancer, both STAT3 and STAT5 have been associated with castration-resistant disease and proposed as therapeutic targets [8,9]. In colon cancer, the association between p-STAT3 and survival varies according to the study, but a high p-STAT3/p-STAT5 ratio indicates bad prognosis [10]. Also in breast cancer, p-STAT5 levels are clearly associated with better prognosis [11]. In liver cancer, STAT5 has ambivalent functions that were recently reviewed by Moriggl and colleagues [12]. Understanding mechanistically how STAT3/5 promote transformation and tumor suppression is important for the eventual design of new treatments. Also, survival data is highly influenced by the response of patients to their treatment and may not always reflect all mechanistic links between STAT3/5 activity and tumor biology. Of note, the effect of any gene is conditioned by the genetic context of gene action. Some genes can clearly exert a tumor suppressor effect in the initial stages of carcinogenesis that is lost when cancer mutations or epigenetic changes inactivate key effectors of these tumor suppressor pathways [13]. Human studies are usually limited to late stage tumors because it is easier to collect samples at that point. Studies in model systems, including primary cells, organoids and mouse models are thus required for a full understanding of how cancer genes work specifically at early stages in tumorigenesis.

3. Mechanisms of Transformation by STAT3/5 Proteins in Solid Cancers

STAT3 and STAT5 promote tumor progression by regulating the expression of cell cycle, survival and pro-inflammatory genes. In addition, they control mitochondrial functions, metabolism and stemness, as discussed below (Figure 2).

3.1. Cell Cycle and Apoptosis

As transcription factors, STAT3 and STAT5 regulate many genes required for cell cycle progression and cell survival. A major target of the transcriptional control of the mammalian cell cycle is cyclin D. STAT3 regulates cyclin D expression in a complex with CD44 and the acetyltransferase p300. The latter acetylates STAT3 promoting its dimerization, nuclear translocation and binding to the cyclin D promoter [25]. Other cell cycle and survival genes regulated by STAT3 include c-MYC (myc proto-oncogene), B-cell lymphoma 2 (BCL2), BCL2L1/BCL-XL (B-cell lymphoma-extra large), MCL1 (Myeloid Cell Leukemia Sequence 1) and BIRC5/survivin [26]. Recent studies combined ChIPSeq with whole transcriptome profiling in ABC DLBCL (activated B cell-like diffuse large B cell lymphoma) cell lines and revealed that STAT3 activates genes in the Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) pathway, the Nuclear Factor Kappa-Light-Chain Enhancer of Activated B-Cells (NF-κB) pathway and the cell cycle regulation pathway, while repressing type I interferon signaling genes [27]. STAT5 also regulates the expression of cell cycle and cell survival genes [13] including AKT1 [28], which encodes a pro-survival kinase.

3.2. Inflammation and Innate Immunity

Although the induction of cell proliferation and cell survival genes by STAT3/5 proteins contribute to their pro-cancer activity, in basal-like breast cancers the major genes associated with STAT3 activation control inflammation and the immune response [29]. Of note, inflammation is initially an adaptive response to pathological insults such as oncogenic stimuli, and it therefore exerts a tumor suppressive function. However, dysregulated inflammation in the long term provides a substrate for tumorigenesis [30]. STAT3 alone or in cooperation with NF-κB regulates the expression of many pro-inflammatory genes [31,32,33]. Starved tumor cells activate NF-κB and STAT3 via endoplasmic reticulum (ER) stress and secrete cytokines that stimulate tumor survival and clonogenic capacity [34]. The coactivation of these two transcription factors amplifies pro-inflammatory gene expression driving cancer-associated inflammation [35]. Of interest, the STAT3-NF-κB complex can repress the expression of DNA Damage Inducible Transcript 3 (DDIT3), an inhibitor of CCAAT Enhancer Binding Protein Beta (CEBPβ), another pro-inflammatory transcription factor [36].
Pharmacological agents that limit inflammation have been proposed for cancer prevention [37]. The use of metformin, a drug widely used to control diabetes, has been associated with a dramatic reduction in cancer incidence in many tissues [38]. Although the primary site of action of this drug is in mitochondria, a consequence of its effects is a potent reduction in the activation of NF-κB and STAT3, suggesting that the promising anticancer actions of metformin are related to its ability to curtail pro-inflammatory gene expression [39,40]. In contrast to STAT3, STAT5B inhibits NF-κB activity in the kidney fibroblast cell line COS by competing with coactivators of transcription [41], while it stimulates NF-κB in leukemia cells [42]. These results suggest the involvement of different regulatory mechanisms of STAT5 in hematopoietic cancers compared with solid cancers.

3.3. Mitochondria

In addition to their canonical roles in inflammation and immunity, STAT3 and STAT5 have been shown to localize to mitochondria. The mitochondrial localization of STAT3 is required for its ability to support malignant transformation in murine embryonic fibroblasts and breast cancer cells [43,44,45,46], and mito-STAT3 regulates mitochondrial metabolism and mitochondrial gene expression [45,47,48,49,50,51]. Several reports have suggested that STAT3 can be imported to mitochondria after phosphorylation on S727 [44,45] or upon acetylation [52,53]. Other studies have revealed that STAT3 mitochondrial translocation is mediated by interactions with Heat Shock Protein 22 (HSP22), Gene Associated with Retinoic and Interferon-Induced Mortality 19 (GRIM-19) or Translocase of Outer Mitochondrial Membrane 20 (TOM20) [54,55,56]. The mRNAs coding for some mitochondrial proteins are translated close to or in physical interaction with the import complex TOM [57,58]. The structural motifs mediating those interactions are located in the 3′ and 5′ UTRs of the mRNAs [59,60] and it will be interesting to investigate whether the mRNA of STAT3 also possesses RNA localization signals (zip codes) to localize in close proximity to mitochondria.
Whereas the role of mitochondrial STAT3 has been extensively studied, the role of STAT5 in mitochondria is less clear. The import of STAT5 to mitochondria is regulated by cytokines [43]. Once imported into the mitochondria, STAT5 binds the D-loop of mitochondrial DNA, although no increase in transcription of mitochondrial genes was observed [61]. Mito-STAT5 is also able to interact with the Pyruvate Dehydrogenase Complex (PDC) and was shown to regulate metabolism towards glycolysis, as observed in cells treated with cytokines [43,61]. In the same line, STAT3 was also shown to interact with the PDC in mitochondria [53].

3.4. Reprogramming and Stemness

The role of STAT3 in stem cell biology was initially recognized due to the requirement for the cytokine LIF to maintain pluripotency in cultures of mouse embryonic stem (ES) cells. STAT3 activation mediates the induction or repression of several genes in mouse ES cells including the pluripotency factors Oct4, Klf4, Tfcp2l1 and polycomb proteins [62,63,64]. Many pluripotency factors, such as Homeobox Protein NANOG, are short-lived proteins. STAT3 controls protein stability by inducing the expression of the deubiquitinase Ubiquitin Specific Peptidase 21 (USP21), stabilizing NANOG in mouse ES cells. Induction of ES cell differentiation promotes the Extracellular Signal-Regulated Kinase (ERK)-dependent phosphorylation of USP21 and its dissociation from NANOG, leading to NANOG degradation [65]. STAT3 also plays a role in the reprogramming of somatic cells into induced pluripotent stem (IPS) cells [66] and it has been suggested that its effects depend on the demethylation of pluripotency factor promoters [67]. STAT3 also activates mitochondrial DNA transcription, promoting oxidative phosphorylation during maintenance and induction of pluripotency [68]. It is thus likely that the ability of STAT3 to stimulate stemness also plays a role in its oncogenic activity.
In many tumors, a subpopulation of cells possess a higher malignant capacity. These so-called tumor-initiating cells are suspected to regenerate the tumor after cancer chemotherapy and express many genes commonly expressed in ES cells [69]. It has been shown that STAT3 is required for the formation of tumor spheres and the viability of the cancer stem cell pool in many different tumors [39,40,70,71,72,73,74,75,76,77,78,79,80,81,82,83]. At least in breast cancer, a critical mechanism stimulated by STAT3 to regulate stemness involves genes in fatty acid oxidation [78,79] and the ability of STAT3 to adjust the levels of reactive oxygen species (ROS) produced in mitochondria [79]. In colorectal cancer cells, STAT3 forms a complex with the stem cell marker CD44 and the p300 acetyltransferase. Acetylation of STAT3 by this complex allows dimerization, nuclear translocation and binding to the promoters of genes required for stemness such as c-MYC and TWIST1 [84].
The role of STAT5 in promoting cancer stemness does not affect many cell types and is mostly confined to hematopoietic cancers [85]. However, Nevalainen and colleagues reported that STAT5B induces stem cell properties in prostate cancer cells [86] in line with the increase in nuclear STAT5A/B observed in these tumors in correlation with bad prognosis [9]. Furthermore, transgenic mice with increased expression of prolactin in prostate epithelial cells displayed increases in the basal/stem cell compartment in association with activation of STAT5. This enrichment of stem cells was partially reversed by depletion of Stat5a/b [87]. The pro-stem cell oncogenic effect of STAT5 in the prostate contrasts with its effects in the mammary gland where STAT5 induces cell differentiation [88]. The ETS transcription factor Elf5 (E74-like factor 5) is a target of the prolactin-STAT5 axis and promotes mammary cell differentiation [89,90,91], supporting the tumor suppressive role of STAT5 in the mammary gland.

4. Tumor Suppressor Functions and Negative Regulation of STAT3/5 Signaling

The oncogenic activity of JAK/STAT signaling is controlled by several molecular barriers that limit the activation of this pathway. They include tyrosine phosphatases, E3 SUMO ligases of the Protein Inhibitor of Activated STAT3 (PIAS) family, E3 ubiquitin ligases and miRNAs. In addition, oncogenic STAT3/5 signaling can activate fail-safe tumor suppressors such as protein of alternative reading frame 19 (p19ARF), Suppressor of Cytokine Signaling 1 (SOCS1) and p53 that trigger apoptosis, ferroptosis and/or senescence in potentially malignant cells (Figure 3). Understanding these different responses to STAT signaling in cancer is important to further distinguish tumors that would benefit from STAT3 or STAT5 inhibitors and those that would not.

4.1. Tyrosine Phosphatases

Activation of STAT3 and STAT5 in tumors is often associated with tyrosine phosphorylation, a modification that can be reverted by several protein tyrosine phosphatases such as PTPN2 (Tyrosine-protein phosphatase non-receptor type 2), PTPN9/MEG2 (Tyrosine-protein phosphatase non-receptor type 9), PTPN11/SHP2 (Tyrosine-protein phosphatase non-receptor type 11) [92,93], CD45 [94] and PTPN6/SHP1 (Tyrosine-protein phosphatase non-receptor type 6) [95]. However, little is known about a possible role of these phosphatases in STAT3 activation in solid tumors. In liver cancers, SHP1 is downregulated in cells with mesenchymal features, and restoring its levels both reduced STAT3 phosphorylation and reversed the mesenchymal phenotype of liver cancer cells [95]. SHP1 and SHP2 also target STAT5 [96,97] but the significance of this regulation in solid tumors remains to be investigated.

4.2. PIAS

The Protein Inhibitor of Activated STAT3 (PIAS3) inhibits STAT3 transcriptional activity. In gliomas, PIAS3 expression is reduced [98]. Mechanistically, SMAD6 promotes PIAS3 degradation, promoting glioma cell growth and stem cell properties [76]. The PIAS proteins have SUMO E3 ligase activity acting on multiple proteins, and so their effects cannot be solely attributed to STAT3 inhibition [99]. Of interest, PIAS3 can bind NF-κB promoting its SUMOylation and inhibiting its activity [100,101], potentially targeting the expression of many pro-inflammatory genes required for tumor progression. Also, PIAS3 binds the N-terminus of p53 and prevents the interaction with its negative regulator MDM2, leading to p53 stabilization [102].

4.3. E3 Ligases

The Golgi resident and BC-box protein TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160) was reported as an E3 ligase that catalyzes STAT3 ubiquitination leading to its proteasome-dependent degradation in myogenic C2C12 cells. The level of TMF/ARA160 was found to be significantly decreased in glioblastoma multiforme tumors, in benign meningioma and in malignant anaplastic meningioma, where STAT3 is known to play an oncogenic role [103]. TMF/ARA160 can also bind and ubiquitinate RELA/NF-κB leading to its proteasome-dependent degradation and a decrease in the expression of inflammatory genes [104]. Furthermore, the ubiquitin ligase TNF receptor associated factor 6 (TRAF6) binds and ubiquitinates STAT3 inhibiting the expression of STAT3 target genes [105]. During oncogene-induced senescence, STAT3 is degraded by the proteasome but the E3 ligase responsible has not been identified [106]. Recent results revealed that the long non-coding RNA (lncRNA) PVT1 (long non-coding RNA encoded by the human PVT1 gene) binds STAT3 and protects it from ubiquitin-dependent degradation in gastric cancer [107]. PVT1 is upregulated in multiple cancers predicting poor prognosis for overall survival [108,109,110].

4.4. MiRNAs

The miRNA miR-124 regulates STAT3 signaling by targeting the mRNAs of interleukin-6 receptor (IL6R) [111] and STAT3 [112,113]. Suppression of this miRNA increases STAT3 phosphorylation and induces transformation in immortalized mouse hepatocytes. Of interest, systemic delivery of miR-124 prevented tumor growth in diethylnitrosamine (DEN)-treated mice, and miR-124 levels were found to be reduced in human hepatocellular carcinomas (HCC) [111]. In gliomas, miR-124 is poorly expressed but upregulation of its expression in glioma cancer stem cells inhibited the STAT3 pathway. In this model, STAT3 mediates immunosuppression, which was relieved upon systemic miR-124 delivery [114]. The circular RNA (circRNA) 100782 is upregulated in pancreatic cancer and its knockdown downregulates all miR-124 targets including IL6R and STAT3. This circRNA binds miR-124 suggesting that it may act as a miRNA sponge [115]. Furthermore, the miRNA miR-1181 also targets STAT3 and is downregulated in pancreatic cancer, predicting poorer overall survival. Overexpression of miR-1181 inhibited tumor formation and stem cell properties of pancreatic cancer cells [116].

4.5. The Suppressor of Cytokine Signaling SOCS

The members of the Suppressor of Cytokine Signaling (SOCS) family are major negative feedback regulators of JAK/STAT signaling and their expression is dysregulated in many human cancers [117,118,119]. These genes provide a barrier for cells with aberrant cytokine activation by inhibiting cytokine signaling [120]. In STAT3 driven cancers, SOCS3 seems to be the most important negative feedback regulator and mouse models of SOCS3 ablation show strong STAT3 activation [119,121,122,123,124]. On the other hand, in solid cancers where STAT5 plays a causal role such as liver and prostate cancer, in addition to SOCS3, SOCS1 is frequently inactivated and mouse models of SOCS1 ablation increase both liver and prostate tumorigenesis [125,126,127,128,129,130,131,132]. In addition to their role as JAK/STAT signaling barriers, SOCS1 and SOCS3 can bind p53 and activate tumor suppressor responses such as senescence and ferroptosis when their expression is induced by aberrant STAT5 signaling in primary cells [133,134,135,136,137,138]. In this way, SOCS1 and SOCS3 also act as fail-safe tumor suppressors in response to aberrant JAK/STAT signaling. So far, the SOCS1-p53-senescence axis has been demonstrated in primary fibroblasts and mammary epithelial cells [133,139,140,141]. This mechanism may explain the better prognosis of some solid cancers with high p-STAT5 [142,143,144] and the high frequency of SOCS1 inactivation in STAT5-driven cancers [125,126,127,128,129,130,131,132]. However, it is difficult to obtain evidence of a senescence tumor-suppression response by studying established tumors that have already circumvented this pathway. Senescence is particularly noticeable in premalignant lesions and benign tumors [40,106,145,146,147,148,149,150], and can be reactivated by cancer chemotherapy [151,152]. For this reason, evidence of STAT5-induced senescence in human cancers is not yet available and should be studied in samples from premalignant tumors or after chemotherapy.
The mechanisms that disable SOCS1 and SOCS3 in human cancers are often epigenetic, mediated either by miRNAs, promoter methylation or protein phosphorylation [127,128,130,131,137,153,154,155,156,157,158,159,160,161,162]. The SRC family of kinases (SFK) phosphorylate SOCS1 at Y80, interfering with p53-SOCS1 interactions. SFK inhibitors can reverse this effect and could be used to restore the SOCS1-p53 axis in tumors where these two proteins remain intact [162]. It is also possible to consider treatments that re-express SOCS1/3 in tumors. Indeed, in liver cancer SOCS3 gene expression can be re-established by drugs that activate the Farnesoid X receptor (FXR) [163,164]. Gene therapy strategies are also under development to re-express SOCS1 or SOCS3 in tumors [165,166,167].

4.6. P19ARF-p53 Pathway

One of the first reports demonstrating that STAT3 can act as a tumor suppressor was shown in glioblastoma multiforme (GBM) [168] where a combination of low Phosphatase and tensin homolog (PTEN) expression and loss of STAT3 in astrocytes increased their tumorigenicity. This observation is in contrast to papers cited above on the requirement for STAT3 to maintain tumor stem cells in GBM [73,75,169]. This could be explained if STAT3 acts early in tumorigenesis as a tumor suppressor but gains oncogenic functions in the context of the cancer genome and epigenome. An interesting mechanism for the tumor suppressor role of STAT3 was recently described in the prostate where STAT3 induces the expression of p19ARF [170]. The latter is a tumor suppressor that activates p53 and inhibits ribosome biogenesis inducing cellular senescence and apoptosis [171,172,173,174]. Loss of STAT3 disrupts this STAT3-ARF-p53 axis and permits tumor progression [175]. STAT3 and other STATs can also induce p21 leading to cell cycle arrest or cellular senescence [176,177]. Further evidence for STAT3 as a tumor suppressor has been reported in lung [178], colon [179,180], thyroid [181], liver [182,183], skin [184], neck [185], nasopharynx, rectum [186], salivary gland [187] and breast cancers [188] but the mechanisms remain to be investigated.

5. Concluding Remarks

Context-dependent activities of STAT3 and STAT5 in solid human cancers justify detailed molecular studies that will clarify the specific molecular mechanisms of action of these two cancer genes. The cancer genome and transcriptome are shaped and selected to favor cancer cell survival and proliferation. Although restoring mutated genes is technologically difficult, reprograming the transcriptome to restore tumor suppression may be feasible. Drugs acting on STAT3/5 and their regulators may restore the control of cell proliferation in cancer cells.

Funding

G.F. is supported by the CIBC chair for breast cancer research at the CRCHUM. This work was funded by a grant from the Canadian Institute of Health and Research (CIHR-MOP229774) to G.F. H.A.N. is supported by the Austrian Science Fund (FWF), under the frame of ERA PerMed (I 4218-B). H.A.N. is also generously supported by a private donation from Liechtenstein.

Acknowledgments

We thank V. Bourdeau for comments.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bromberg, J.; Darnell, J.E., Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000, 19, 2468–2473. [Google Scholar] [CrossRef] [PubMed]
  2. Kandoth, C.; McLellan, M.D.; Vandin, F.; Ye, K.; Niu, B.; Lu, C.; Xie, M.; Zhang, Q.; McMichael, J.F.; Wyczalkowski, M.A.; et al. Mutational landscape and significance across 12 major cancer types. Nature 2013, 502, 333–339. [Google Scholar] [CrossRef] [PubMed]
  3. de Araujo, E.D.; Erdogan, F.; Neubauer, H.A.; Meneksedag-Erol, D.; Manaswiyoungkul, P.; Eram, M.S.; Seo, H.S.; Qadree, A.K.; Israelian, J.; Orlova, A.; et al. Structural and functional consequences of the STAT5B(N642H) driver mutation. Nat. Commun. 2019, 10, 2517. [Google Scholar] [CrossRef] [PubMed]
  4. Koskela, H.L.; Eldfors, S.; Ellonen, P.; van Adrichem, A.J.; Kuusanmaki, H.; Andersson, E.I.; Lagstrom, S.; Clemente, M.J.; Olson, T.; Jalkanen, S.E.; et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N. Engl. J. Med. 2012, 366, 1905–1913. [Google Scholar] [CrossRef] [PubMed]
  5. Carpenter, R.L.; Lo, H.W. STAT3 Target Genes Relevant to Human Cancers. Cancers (Basel) 2014, 6, 897–925. [Google Scholar] [CrossRef]
  6. Basham, B.; Sathe, M.; Grein, J.; McClanahan, T.; D’Andrea, A.; Lees, E.; Rascle, A. In vivo identification of novel STAT5 target genes. Nucleic Acids Res. 2008, 36, 3802–3818. [Google Scholar] [CrossRef]
  7. Wu, P.; Wu, D.; Zhao, L.; Huang, L.; Shen, G.; Huang, J.; Chai, Y. Prognostic role of STAT3 in solid tumors: A systematic review and meta-analysis. Oncotarget 2016, 7, 19863–19883. [Google Scholar] [CrossRef]
  8. Mohanty, S.K.; Yagiz, K.; Pradhan, D.; Luthringer, D.J.; Amin, M.B.; Alkan, S.; Cinar, B. STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer. Oncotarget 2017, 8, 85997–86010. [Google Scholar] [CrossRef]
  9. Mirtti, T.; Leiby, B.E.; Abdulghani, J.; Aaltonen, E.; Pavela, M.; Mamtani, A.; Alanen, K.; Egevad, L.; Granfors, T.; Josefsson, A.; et al. Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy. Hum. Pathol. 2013, 44, 310–319. [Google Scholar] [CrossRef]
  10. Klupp, F.; Diers, J.; Kahlert, C.; Neumann, L.; Halama, N.; Franz, C.; Schmidt, T.; Lasitschka, F.; Warth, A.; Weitz, J.; et al. Expressional STAT3/STAT5 Ratio is an Independent Prognostic Marker in Colon Carcinoma. Ann. Surg. Oncol. 2015, 22, S1548–S1555. [Google Scholar] [CrossRef]
  11. Peck, A.R.; Witkiewicz, A.K.; Liu, C.; Stringer, G.A.; Klimowicz, A.C.; Pequignot, E.; Freydin, B.; Tran, T.H.; Yang, N.; Rosenberg, A.L.; et al. Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J. Clin. Oncol. 2011, 29, 2448–2458. [Google Scholar] [CrossRef] [PubMed]
  12. Kaltenecker, D.; Themanns, M.; Mueller, K.M.; Spirk, K.; Suske, T.; Merkel, O.; Kenner, L.; Luis, A.; Kozlov, A.; Haybaeck, J.; et al. Hepatic growth hormone-JAK2-STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression. Cytokine 2018. [Google Scholar] [CrossRef] [PubMed]
  13. Ferbeyre, G.; Moriggl, R. The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim. Biophys. Acta 2011, 1815, 104–114. [Google Scholar] [CrossRef] [PubMed]
  14. Xu, Y.H.; Lu, S. A meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with non-small-cell lung cancer. Eur. J. Surg. Oncol. 2014, 40, 311–317. [Google Scholar] [CrossRef] [PubMed]
  15. Sun, Z.G.; Zhang, M.; Yang, F.; Gao, W.; Wang, Z.; Zhu, L.M. Clinical and prognostic significance of signal transducer and activator of transcription 3 and mucin 1 in patients with non-small cell lung cancer following surgery. Oncol. Lett. 2018, 15, 4278–4288. [Google Scholar] [CrossRef] [PubMed]
  16. Tong, M.; Wang, J.; Jiang, N.; Pan, H.; Li, D. Correlation between p-STAT3 overexpression and prognosis in lung cancer: A systematic review and meta-analysis. PLoS ONE 2017, 12, e0182282. [Google Scholar] [CrossRef] [PubMed]
  17. Koperek, O.; Aumayr, K.; Schindl, M.; Werba, G.; Soleiman, A.; Schoppmann, S.; Sahora, K.; Birner, P. Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma. APMIS 2014, 122, 476–481. [Google Scholar] [CrossRef] [PubMed]
  18. Liang, C.; Xu, Y.; Ge, H.; Li, G.; Wu, J. Clinicopathological significance and prognostic role of p-STAT3 in patients with hepatocellular carcinoma. Onco-Targets Ther. 2018, 11, 1203–1214. [Google Scholar] [CrossRef]
  19. Liu, Y.; Huang, J.; Li, W.; Chen, Y.; Liu, X.; Wang, J. Meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with breast cancer. Oncotarget 2018, 9, 13060–13067. [Google Scholar] [CrossRef] [PubMed]
  20. Sonnenblick, A.; Salgado, R.; Brohee, S.; Zahavi, T.; Peretz, T.; Van den Eynden, G.; Rouas, G.; Salmon, A.; Francis, P.A.; Di Leo, A.; et al. p-STAT3 in luminal breast cancer: Integrated RNA-protein pooled analysis and results from the BIG 2-98 phase III trial. Int. J. Oncol. 2018, 52, 424–432. [Google Scholar] [CrossRef]
  21. Lin, G.S.; Chen, Y.P.; Lin, Z.X.; Wang, X.F.; Zheng, Z.Q.; Chen, L. STAT3 serine 727 phosphorylation influences clinical outcome in glioblastoma. Int. J. Clin. Exp. Pathol. 2014, 7, 3141–3149. [Google Scholar]
  22. Vilardell, J.; Alcaraz, E.; Sarro, E.; Trilla, E.; Cuadros, T.; de Torres, I.; Plana, M.; Ramon, Y.C.S.; Pinna, L.A.; Ruzzene, M.; et al. Under-expression of CK2beta subunit in ccRCC represents a complementary biomarker of p-STAT3 Ser727 that correlates with patient survival. Oncotarget 2018, 9, 5736–5751. [Google Scholar] [CrossRef] [PubMed]
  23. Kusaba, T.; Nakayama, T.; Yamazumi, K.; Yakata, Y.; Yoshizaki, A.; Inoue, K.; Nagayasu, T.; Sekine, I. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol. Rep. 2006, 15, 1445–1451. [Google Scholar] [CrossRef]
  24. Morikawa, T.; Baba, Y.; Yamauchi, M.; Kuchiba, A.; Nosho, K.; Shima, K.; Tanaka, N.; Huttenhower, C.; Frank, D.A.; Fuchs, C.S.; et al. STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin. Cancer Res. 2011, 17, 1452–1462. [Google Scholar] [CrossRef]
  25. Lee, J.L.; Wang, M.J.; Chen, J.Y. Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. J. Cell Biol. 2009, 185, 949–957. [Google Scholar] [CrossRef] [PubMed]
  26. Banerjee, K.; Resat, H. Constitutive activation of STAT3 in breast cancer cells: A review. Int. J. Cancer 2016, 138, 2570–2578. [Google Scholar] [CrossRef] [PubMed]
  27. Lu, L.; Zhu, F.; Zhang, M.; Li, Y.; Drennan, A.C.; Kimpara, S.; Rumball, I.; Selzer, C.; Cameron, H.; Kellicut, A.; et al. Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA 2018, 115, E498–E505. [Google Scholar] [CrossRef] [PubMed]
  28. Creamer, B.A.; Sakamoto, K.; Schmidt, J.W.; Triplett, A.A.; Moriggl, R.; Wagner, K.U. Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1. Mol. Cell. Biol. 2010, 30, 2957–2970. [Google Scholar] [CrossRef]
  29. Tell, R.W.; Horvath, C.M. Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors. Proc. Natl. Acad. Sci. USA 2014, 111, 12787–12792. [Google Scholar] [CrossRef]
  30. Karki, R.; Kanneganti, T.D. Diverging inflammasome signals in tumorigenesis and potential targeting. Nat. Rev. Cancer 2019, 19, 197–214. [Google Scholar] [CrossRef]
  31. Martincuks, A.; Andryka, K.; Kuster, A.; Schmitz-Van de Leur, H.; Komorowski, M.; Muller-Newen, G. Nuclear translocation of STAT3 and NF-kappaB are independent of each other but NF-kappaB supports expression and activation of STAT3. Cell. Signal. 2017, 32, 36–47. [Google Scholar] [CrossRef] [PubMed]
  32. Goldstein, I.; Paakinaho, V.; Baek, S.; Sung, M.H.; Hager, G.L. Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading. Nat. Commun. 2017, 8, 1849. [Google Scholar] [CrossRef] [PubMed]
  33. Grivennikov, S.I.; Karin, M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010, 21, 11–19. [Google Scholar] [CrossRef] [PubMed]
  34. Yoon, S.; Woo, S.U.; Kang, J.H.; Kim, K.; Shin, H.J.; Gwak, H.S.; Park, S.; Chwae, Y.J. NF-kappaB and STAT3 cooperatively induce IL6 in starved cancer cells. Oncogene 2012, 31, 3467–3481. [Google Scholar] [CrossRef] [PubMed]
  35. Atsumi, T.; Singh, R.; Sabharwal, L.; Bando, H.; Meng, J.; Arima, Y.; Yamada, M.; Harada, M.; Jiang, J.J.; Kamimura, D.; et al. Inflammation amplifier, a new paradigm in cancer biology. Cancer Res. 2014, 74, 8–14. [Google Scholar] [CrossRef] [PubMed]
  36. Canino, C.; Luo, Y.; Marcato, P.; Blandino, G.; Pass, H.I.; Cioce, M. A STAT3-NFkB/DDIT3/CEBPbeta axis modulates ALDH1A3 expression in chemoresistant cell subpopulations. Oncotarget 2015, 6, 12637–12653. [Google Scholar] [CrossRef] [PubMed]
  37. Thi, H.T.H.; Hong, S. Inflammasome as a Therapeutic Target for Cancer Prevention and Treatment. J. Cancer Prev. 2017, 22, 62–73. [Google Scholar] [CrossRef] [PubMed]
  38. Pollak, M.N. Investigating metformin for cancer prevention and treatment: The end of the beginning. Cancer Discov. 2012, 2, 778–790. [Google Scholar] [CrossRef]
  39. Hirsch, H.A.; Iliopoulos, D.; Struhl, K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl. Acad. Sci. USA 2013, 110, 972–977. [Google Scholar] [CrossRef]
  40. Deschenes-Simard, X.; Parisotto, M.; Rowell, M.C.; Le Calve, B.; Igelmann, S.; Moineau-Vallee, K.; Saint-Germain, E.; Kalegari, P.; Bourdeau, V.; Kottakis, F.; et al. Circumventing senescence is associated with stem cell properties and metformin sensitivity. Aging Cell 2019. [Google Scholar] [CrossRef]
  41. Luo, G.; Yu-Lee, L. Stat5b inhibits NFkappaB-mediated signaling. Mol. Endocrinol. 2000, 14, 114–123. [Google Scholar] [CrossRef] [PubMed]
  42. Kawashima, T.; Murata, K.; Akira, S.; Tonozuka, Y.; Minoshima, Y.; Feng, S.; Kumagai, H.; Tsuruga, H.; Ikeda, Y.; Asano, S.; et al. STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-kappaB p65. J. Immunol. 2001, 167, 3652–3660. [Google Scholar] [CrossRef] [PubMed]
  43. Chueh, F.Y.; Leong, K.F.; Yu, C.L. Mitochondrial translocation of signal transducer and activator of transcription 5 (STAT5) in leukemic T cells and cytokine-stimulated cells. Biochem. Biophys. Res. Commun. 2010, 402, 778–783. [Google Scholar] [CrossRef] [PubMed]
  44. Gough, D.J.; Corlett, A.; Schlessinger, K.; Wegrzyn, J.; Larner, A.C.; Levy, D.E. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 2009, 324, 1713–1716. [Google Scholar] [CrossRef] [PubMed]
  45. Wegrzyn, J.; Potla, R.; Chwae, Y.J.; Sepuri, N.B.; Zhang, Q.; Koeck, T.; Derecka, M.; Szczepanek, K.; Szelag, M.; Gornicka, A.; et al. Function of mitochondrial Stat3 in cellular respiration. Science 2009, 323, 793–797. [Google Scholar] [CrossRef] [PubMed]
  46. Zhang, Q.; Raje, V.; Yakovlev, V.A.; Yacoub, A.; Szczepanek, K.; Meier, J.; Derecka, M.; Chen, Q.; Hu, Y.; Sisler, J.; et al. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J. Biol. Chem. 2013, 288, 31280–31288. [Google Scholar] [CrossRef] [PubMed]
  47. Macias, E.; Rao, D.; Carbajal, S.; Kiguchi, K.; DiGiovanni, J. Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. J. Investig. Dermatol. 2014, 134, 1971–1980. [Google Scholar] [CrossRef]
  48. Rincon, M.; Pereira, F.V. A New Perspective: Mitochondrial Stat3 as a Regulator for Lymphocyte Function. Int. J. Mol. Sci. 2018, 19, 1656. [Google Scholar] [CrossRef]
  49. Avalle, L.; Poli, V. Nucleus, Mitochondrion, or Reticulum? STAT3 a La Carte. Int. J. Mol. Sci. 2018, 19, 2820. [Google Scholar] [CrossRef]
  50. Luo, D.; Fraga-Lauhirat, M.; Millings, J.; Ho, C.; Villarreal, E.M.; Fletchinger, T.C.; Bonfiglio, J.V.; Mata, L.; Nemesure, M.D.; Bartels, L.E.; et al. Phospho-valproic acid (MDC-1112) suppresses glioblastoma growth in preclinical models through the inhibition of STAT3 phosphorylation. Carcinogenesis 2019. [Google Scholar] [CrossRef]
  51. Sala, D.; Cunningham, T.J.; Stec, M.J.; Etxaniz, U.; Nicoletti, C.; Dall’Agnese, A.; Puri, P.L.; Duester, G.; Latella, L.; Sacco, A. The Stat3-Fam3a axis promotes muscle stem cell myogenic lineage progression by inducing mitochondrial respiration. Nat. Commun. 2019, 10, 1796. [Google Scholar] [CrossRef]
  52. Bernier, M.; Paul, R.K.; Martin-Montalvo, A.; Scheibye-Knudsen, M.; Song, S.; He, H.J.; Armour, S.M.; Hubbard, B.P.; Bohr, V.A.; Wang, L.; et al. Negative regulation of STAT3 protein-mediated cellular respiration by SIRT1 protein. J. Biol. Chem. 2011, 286, 19270–19279. [Google Scholar] [CrossRef]
  53. Xu, Y.S.; Liang, J.J.; Wang, Y.; Zhao, X.J.; Xu, L.; Xu, Y.Y.; Zou, Q.C.; Zhang, J.M.; Tu, C.E.; Cui, Y.G.; et al. STAT3 Undergoes Acetylation-dependent Mitochondrial Translocation to Regulate Pyruvate Metabolism. Sci. Rep. 2016, 6, 39517. [Google Scholar] [CrossRef]
  54. Boengler, K.; Hilfiker-Kleiner, D.; Heusch, G.; Schulz, R. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res. Cardiol. 2010, 105, 771–785. [Google Scholar] [CrossRef] [PubMed]
  55. Tammineni, P.; Anugula, C.; Mohammed, F.; Anjaneyulu, M.; Larner, A.C.; Sepuri, N.B. The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. J. Biol. Chem. 2013, 288, 4723–4732. [Google Scholar] [CrossRef]
  56. Qiu, H.; Lizano, P.; Laure, L.; Sui, X.; Rashed, E.; Park, J.Y.; Hong, C.; Gao, S.; Holle, E.; Morin, D.; et al. H11 kinase/heat shock protein 22 deletion impairs both nuclear and mitochondrial functions of STAT3 and accelerates the transition into heart failure on cardiac overload. Circulation 2011, 124, 406–415. [Google Scholar] [CrossRef] [PubMed]
  57. Gadir, N.; Haim-Vilmovsky, L.; Kraut-Cohen, J.; Gerst, J.E. Localization of mRNAs coding for mitochondrial proteins in the yeast Saccharomyces cerevisiae. RNA 2011, 17, 1551–1565. [Google Scholar] [CrossRef]
  58. Fox, T.D. Mitochondrial protein synthesis, import, and assembly. Genetics 2012, 192, 1203–1234. [Google Scholar] [CrossRef]
  59. Zhang, Y.; Chen, Y.; Gucek, M.; Xu, H. The mitochondrial outer membrane protein MDI promotes local protein synthesis and mtDNA replication. EMBO J. 2016, 35, 1045–1057. [Google Scholar] [CrossRef]
  60. Hansen, K.G.; Herrmann, J.M. Transport of Proteins into Mitochondria. Protein J. 2019. [Google Scholar] [CrossRef]
  61. Richard, A.J.; Hang, H.; Stephens, J.M. Pyruvate dehydrogenase complex (PDC) subunits moonlight as interaction partners of phosphorylated STAT5 in adipocytes and adipose tissue. J. Biol. Chem. 2017, 292, 19733–19742. [Google Scholar] [CrossRef] [PubMed]
  62. Kidder, B.L.; Yang, J.; Palmer, S. Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells. PLoS ONE 2008, 3, e3932. [Google Scholar] [CrossRef] [PubMed]
  63. Hall, J.; Guo, G.; Wray, J.; Eyres, I.; Nichols, J.; Grotewold, L.; Morfopoulou, S.; Humphreys, P.; Mansfield, W.; Walker, R.; et al. Oct4 and LIF/Stat3 additively induce Kruppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 2009, 5, 597–609. [Google Scholar] [CrossRef] [PubMed]
  64. Ye, S.; Li, P.; Tong, C.; Ying, Q.L. Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1. EMBO J. 2013, 32, 2548–2560. [Google Scholar] [CrossRef] [PubMed]
  65. Jin, J.; Liu, J.; Chen, C.; Liu, Z.; Jiang, C.; Chu, H.; Pan, W.; Wang, X.; Zhang, L.; Li, B.; et al. The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog. Nat. Commun. 2016, 7, 13594. [Google Scholar] [CrossRef] [PubMed]
  66. Yang, J.; van Oosten, A.L.; Theunissen, T.W.; Guo, G.; Silva, J.C.; Smith, A. Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell 2010, 7, 319–328. [Google Scholar] [CrossRef]
  67. Tang, Y.; Luo, Y.; Jiang, Z.; Ma, Y.; Lin, C.J.; Kim, C.; Carter, M.G.; Amano, T.; Park, J.; Kish, S.; et al. Jak/Stat3 signaling promotes somatic cell reprogramming by epigenetic regulation. Stem Cells 2012, 30, 2645–2656. [Google Scholar] [CrossRef]
  68. Carbognin, E.; Betto, R.M.; Soriano, M.E.; Smith, A.G.; Martello, G. Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency. EMBO J. 2016, 35, 618–634. [Google Scholar] [CrossRef]
  69. Ben-Porath, I.; Thomson, M.W.; Carey, V.J.; Ge, R.; Bell, G.W.; Regev, A.; Weinberg, R.A. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 2008, 40, 499–507. [Google Scholar] [CrossRef]
  70. Zhou, J.; Wulfkuhle, J.; Zhang, H.; Gu, P.; Yang, Y.; Deng, J.; Margolick, J.B.; Liotta, L.A.; Petricoin, E., 3rd; Zhang, Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc. Natl. Acad. Sci. USA 2007, 104, 16158–16163. [Google Scholar] [CrossRef]
  71. Marotta, L.L.; Almendro, V.; Marusyk, A.; Shipitsin, M.; Schemme, J.; Walker, S.R.; Bloushtain-Qimron, N.; Kim, J.J.; Choudhury, S.A.; Maruyama, R.; et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. J. Clin. Investig. 2011, 121, 2723–2735. [Google Scholar] [CrossRef] [PubMed]
  72. Iliopoulos, D.; Hirsch, H.A.; Struhl, K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009, 139, 693–706. [Google Scholar] [CrossRef] [PubMed]
  73. Gong, A.H.; Wei, P.; Zhang, S.; Yao, J.; Yuan, Y.; Zhou, A.D.; Lang, F.F.; Heimberger, A.B.; Rao, G.; Huang, S. FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells. Cancer Res. 2015, 75, 2337–2348. [Google Scholar] [CrossRef] [PubMed]
  74. Peng, L.; Jiang, D. Resveratrol eliminates cancer stem cells of osteosarcoma by STAT3 pathway inhibition. PLoS ONE 2018, 13, e0205918. [Google Scholar] [CrossRef] [PubMed]
  75. Man, J.; Yu, X.; Huang, H.; Zhou, W.; Xiang, C.; Huang, H.; Miele, L.; Liu, Z.; Bebek, G.; Bao, S.; et al. Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells. Cell Stem Cell 2018, 22, 104–118.e6. [Google Scholar] [CrossRef] [PubMed]
  76. Jiao, J.; Zhang, R.; Li, Z.; Yin, Y.; Fang, X.; Ding, X.; Cai, Y.; Yang, S.; Mu, H.; Zong, D.; et al. Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition. Nat. Commun. 2018, 9, 2504. [Google Scholar] [CrossRef] [PubMed]
  77. He, W.; Wu, J.; Shi, J.; Huo, Y.M.; Dai, W.; Geng, J.; Lu, P.; Yang, M.W.; Fang, Y.; Wang, W.; et al. IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer. Cancer Res. 2018, 78, 3293–3305. [Google Scholar] [CrossRef]
  78. Wang, T.; Fahrmann, J.F.; Lee, H.; Li, Y.J.; Tripathi, S.C.; Yue, C.; Zhang, C.; Lifshitz, V.; Song, J.; Yuan, Y.; et al. JAK/STAT3-Regulated Fatty Acid beta-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab. 2018, 27, 136–150. [Google Scholar] [CrossRef]
  79. Kitajima, S.; Yoshida, A.; Kohno, S.; Li, F.; Suzuki, S.; Nagatani, N.; Nishimoto, Y.; Sasaki, N.; Muranaka, H.; Wan, Y.; et al. The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. Oncogene 2017, 36, 5145–5157. [Google Scholar] [CrossRef]
  80. Chen, M.W.; Yang, S.T.; Chien, M.H.; Hua, K.T.; Wu, C.J.; Hsiao, S.M.; Lin, H.; Hsiao, M.; Su, J.L.; Wei, L.H. The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer. Cancer Res. 2017, 77, 1955–1967. [Google Scholar] [CrossRef]
  81. Schroeder, A.; Herrmann, A.; Cherryholmes, G.; Kowolik, C.; Buettner, R.; Pal, S.; Yu, H.; Muller-Newen, G.; Jove, R. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 2014, 74, 1227–1237. [Google Scholar] [CrossRef] [PubMed]
  82. Tang, Y.; Kitisin, K.; Jogunoori, W.; Li, C.; Deng, C.X.; Mueller, S.C.; Ressom, H.W.; Rashid, A.; He, A.R.; Mendelson, J.S.; et al. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling. Proc. Natl. Acad. Sci. USA 2008, 105, 2445–2450. [Google Scholar] [CrossRef] [PubMed]
  83. Thiagarajan, P.S.; Zheng, Q.; Bhagrath, M.; Mulkearns-Hubert, E.E.; Myers, M.G.; Lathia, J.D.; Reizes, O. STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance. Endocr. Relat. Cancer 2017, 24, 415–426. [Google Scholar] [CrossRef] [PubMed]
  84. Su, Y.J.; Lai, H.M.; Chang, Y.W.; Chen, G.Y.; Lee, J.L. Direct reprogramming of stem cell properties in colon cancer cells by CD44. EMBO J. 2011, 30, 3186–3199. [Google Scholar] [CrossRef] [PubMed]
  85. Schepers, H.; van Gosliga, D.; Wierenga, A.T.; Eggen, B.J.; Schuringa, J.J.; Vellenga, E. STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells. Blood 2007, 110, 2880–2888. [Google Scholar] [CrossRef] [PubMed]
  86. Talati, P.G.; Gu, L.; Ellsworth, E.M.; Girondo, M.A.; Trerotola, M.; Hoang, D.T.; Leiby, B.; Dagvadorj, A.; McCue, P.A.; Lallas, C.D.; et al. Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer. Am. J. Pathol. 2015, 185, 2505–2522. [Google Scholar] [CrossRef] [PubMed]
  87. Boutillon, F.; Pigat, N.; Sala, L.S.; Reyes-Gomez, E.; Moriggl, R.; Guidotti, J.E.; Goffin, V. STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice. Cancers (Basel) 2019, 11, 929. [Google Scholar] [CrossRef] [PubMed]
  88. Liu, X.; Robinson, G.W.; Wagner, K.U.; Garrett, L.; Wynshaw-Boris, A.; Hennighausen, L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 1997, 11, 179–186. [Google Scholar] [CrossRef] [PubMed]
  89. Oakes, S.R.; Naylor, M.J.; Asselin-Labat, M.L.; Blazek, K.D.; Gardiner-Garden, M.; Hilton, H.N.; Kazlauskas, M.; Pritchard, M.A.; Chodosh, L.A.; Pfeffer, P.L.; et al. The ETS transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 2008, 22, 581–586. [Google Scholar] [CrossRef] [PubMed]
  90. Metser, G.; Shin, H.Y.; Wang, C.; Yoo, K.H.; Oh, S.; Villarino, A.V.; O’Shea, J.J.; Kang, K.; Hennighausen, L. An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res. 2016, 44, 1052–1063. [Google Scholar] [CrossRef] [PubMed]
  91. Stute, P.; Sielker, S.; Wood, C.E.; Register, T.C.; Lees, C.J.; Dewi, F.N.; Williams, J.K.; Wagner, J.D.; Stefenelli, U.; Cline, J.M. Life stage differences in mammary gland gene expression profile in non-human primates. Breast Cancer Res. Treat. 2012, 133, 617–634. [Google Scholar] [CrossRef] [PubMed]
  92. Kim, M.; Morales, L.D.; Jang, I.S.; Cho, Y.Y.; Kim, D.J. Protein Tyrosine Phosphatases as Potential Regulators of STAT3 Signaling. Int. J. Mol. Sci. 2018, 19, 2708. [Google Scholar] [CrossRef] [PubMed]
  93. Huang, Y.; Wang, J.; Cao, F.; Jiang, H.; Li, A.; Li, J.; Qiu, L.; Shen, H.; Chang, W.; Zhou, C.; et al. SHP2 associates with nuclear localization of STAT3: Significance in progression and prognosis of colorectal cancer. Sci. Rep. 2017, 7, 17597. [Google Scholar] [CrossRef] [PubMed]
  94. Kumar, V.; Cheng, P.; Condamine, T.; Mony, S.; Languino, L.R.; McCaffrey, J.C.; Hockstein, N.; Guarino, M.; Masters, G.; Penman, E.; et al. CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. Immunity 2016, 44, 303–315. [Google Scholar] [CrossRef] [PubMed]
  95. Fan, L.C.; Shiau, C.W.; Tai, W.T.; Hung, M.H.; Chu, P.Y.; Hsieh, F.S.; Lin, H.; Yu, H.C.; Chen, K.F. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene 2015, 34, 5252–5263. [Google Scholar] [CrossRef] [PubMed]
  96. Chen, Y.; Wen, R.; Yang, S.; Schuman, J.; Zhang, E.E.; Yi, T.; Feng, G.S.; Wang, D. Identification of Shp-2 as a Stat5A phosphatase. J. Biol. Chem. 2003, 278, 16520–16527. [Google Scholar] [CrossRef]
  97. Xiao, W.; Ando, T.; Wang, H.Y.; Kawakami, Y.; Kawakami, T. Lyn- and PLC-beta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease. Blood 2010, 116, 6003–6013. [Google Scholar] [CrossRef]
  98. Brantley, E.C.; Nabors, L.B.; Gillespie, G.Y.; Choi, Y.H.; Palmer, C.A.; Harrison, K.; Roarty, K.; Benveniste, E.N. Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: Implications for STAT-3 activation and gene expression. Clin. Cancer Res. 2008, 14, 4694–4704. [Google Scholar] [CrossRef] [PubMed]
  99. Sundvall, M.; Korhonen, A.; Vaparanta, K.; Anckar, J.; Halkilahti, K.; Salah, Z.; Aqeilan, R.I.; Palvimo, J.J.; Sistonen, L.; Elenius, K. Protein inhibitor of activated STAT3 (PIAS3) protein promotes SUMOylation and nuclear sequestration of the intracellular domain of ErbB4 protein. J. Biol. Chem. 2012, 287, 23216–23226. [Google Scholar] [CrossRef]
  100. Jang, H.D.; Yoon, K.; Shin, Y.J.; Kim, J.; Lee, S.Y. PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit. J. Biol. Chem. 2004, 279, 24873–24880. [Google Scholar] [CrossRef]
  101. Liu, Y.; Bridges, R.; Wortham, A.; Kulesz-Martin, M. NF-kappaB repression by PIAS3 mediated RelA SUMOylation. PLoS ONE 2012, 7, e37636. [Google Scholar] [CrossRef]
  102. Zhao, Z.; Wu, L.; Shi, H.; Wu, C. p53 Nterminal binding and stabilisation by PIAS3 inhibits MDM2induced p53 ubiquitination and regulates cell growth. Mol. Med. Rep. 2014, 9, 1903–1908. [Google Scholar] [CrossRef] [PubMed]
  103. Perry, E.; Tsruya, R.; Levitsky, P.; Pomp, O.; Taller, M.; Weisberg, S.; Parris, W.; Kulkarni, S.; Malovani, H.; Pawson, T.; et al. TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3. Oncogene 2004, 23, 8908–8919. [Google Scholar] [CrossRef] [PubMed]
  104. Abrham, G.; Volpe, M.; Shpungin, S.; Nir, U. TMF/ARA160 downregulates proangiogenic genes and attenuates the progression of PC3 xenografts. Int. J. Cancer 2009, 125, 43–53. [Google Scholar] [CrossRef] [PubMed]
  105. Wei, J.; Yuan, Y.; Jin, C.; Chen, H.; Leng, L.; He, F.; Wang, J. The ubiquitin ligase TRAF6 negatively regulates the JAK-STAT signaling pathway by binding to STAT3 and mediating its ubiquitination. PLoS ONE 2012, 7, e49567. [Google Scholar] [CrossRef] [PubMed]
  106. Deschenes-Simard, X.; Gaumont-Leclerc, M.F.; Bourdeau, V.; Lessard, F.; Moiseeva, O.; Forest, V.; Igelmann, S.; Mallette, F.A.; Saba-El-Leil, M.K.; Meloche, S.; et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev. 2013, 27, 900–915. [Google Scholar] [CrossRef] [PubMed]
  107. Zhao, J.; Du, P.; Cui, P.; Qin, Y.; Hu, C.; Wu, J.; Zhou, Z.; Zhang, W.; Qin, L.; Huang, G. LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. Oncogene 2018. [Google Scholar] [CrossRef] [PubMed]
  108. You, L.; Chang, D.; Du, H.Z.; Zhao, Y.P. Genome-wide screen identifies PVT1 as a regulator of Gemcitabine sensitivity in human pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2011, 407, 1–6. [Google Scholar] [CrossRef] [PubMed]
  109. Xie, Z.; Chen, X.; Li, J.; Guo, Y.; Li, H.; Pan, X.; Jiang, J.; Liu, H.; Wu, B. Salivary HOTAIR and PVT1 as novel biomarkers for early pancreatic cancer. Oncotarget 2016, 7, 25408–25419. [Google Scholar] [CrossRef]
  110. Pan, X.; Li, B.; Fan, N.; Li, J.; Cai, F.; Zhao, G.; Zheng, G.; Gao, C. Long Noncoding RNA PVT1 as a Potent Predictor of Prognosis in Cancers: A Meta-Analysis. Clin. Lab. 2017, 63, 1657–1666. [Google Scholar] [CrossRef]
  111. Hatziapostolou, M.; Polytarchou, C.; Aggelidou, E.; Drakaki, A.; Poultsides, G.A.; Jaeger, S.A.; Ogata, H.; Karin, M.; Struhl, K.; Hadzopoulou-Cladaras, M.; et al. An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 2011, 147, 1233–1247. [Google Scholar] [CrossRef] [PubMed]
  112. Cai, B.; Li, J.; Wang, J.; Luo, X.; Ai, J.; Liu, Y.; Wang, N.; Liang, H.; Zhang, M.; Chen, N.; et al. microRNA-124 regulates cardiomyocyte differentiation of bone marrow-derived mesenchymal stem cells via targeting STAT3 signaling. Stem Cells 2012, 30, 1746–1755. [Google Scholar] [CrossRef] [PubMed]
  113. Zhang, J.; Lu, Y.; Yue, X.; Li, H.; Luo, X.; Wang, Y.; Wang, K.; Wan, J. MiR-124 suppresses growth of human colorectal cancer by inhibiting STAT3. PLoS ONE 2013, 8, e70300. [Google Scholar] [CrossRef] [PubMed]
  114. Wei, J.; Wang, F.; Kong, L.Y.; Xu, S.; Doucette, T.; Ferguson, S.D.; Yang, Y.; McEnery, K.; Jethwa, K.; Gjyshi, O.; et al. miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res. 2013, 73, 3913–3926. [Google Scholar] [CrossRef] [PubMed]
  115. Chen, G.; Shi, Y.; Zhang, Y.; Sun, J. CircRNA_100782 regulates pancreatic carcinoma proliferation through the IL6-STAT3 pathway. Onco-Targets Ther. 2017, 10, 5783–5794. [Google Scholar] [CrossRef]
  116. Jiang, J.; Li, Z.; Yu, C.; Chen, M.; Tian, S.; Sun, C. MiR-1181 inhibits stem cell-like phenotypes and suppresses SOX2 and STAT3 in human pancreatic cancer. Cancer Lett. 2015, 356, 962–970. [Google Scholar] [CrossRef] [PubMed]
  117. Jiang, M.; Zhang, W.W.; Liu, P.; Yu, W.; Liu, T.; Yu, J. Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment. Front. Immunol. 2017, 8, 70. [Google Scholar] [CrossRef]
  118. Ghafouri-Fard, S.; Oskooei, V.K.; Azari, I.; Taheri, M. Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer. World J. Surg. Oncol. 2018, 16, 226. [Google Scholar] [CrossRef]
  119. He, B.; You, L.; Uematsu, K.; Zang, K.; Xu, Z.; Lee, A.Y.; Costello, J.F.; McCormick, F.; Jablons, D.M. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc. Natl. Acad. Sci. USA 2003, 100, 14133–14138. [Google Scholar] [CrossRef]
  120. Inagaki-Ohara, K.; Kondo, T.; Ito, M.; Yoshimura, A. SOCS, inflammation, and cancer. JAKSTAT 2013, 2, e24053. [Google Scholar] [CrossRef]
  121. Suzuki, A.; Hanada, T.; Mitsuyama, K.; Yoshida, T.; Kamizono, S.; Hoshino, T.; Kubo, M.; Yamashita, A.; Okabe, M.; Takeda, K.; et al. CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J. Exp. Med. 2001, 193, 471–481. [Google Scholar] [CrossRef] [PubMed]
  122. Niwa, Y.; Kanda, H.; Shikauchi, Y.; Saiura, A.; Matsubara, K.; Kitagawa, T.; Yamamoto, J.; Kubo, T.; Yoshikawa, H. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 2005, 24, 6406–6417. [Google Scholar] [CrossRef] [PubMed]
  123. Rigby, R.J.; Simmons, J.G.; Greenhalgh, C.J.; Alexander, W.S.; Lund, P.K. Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene 2007, 26, 4833–4841. [Google Scholar] [CrossRef] [PubMed]
  124. Lesina, M.; Kurkowski, M.U.; Ludes, K.; Rose-John, S.; Treiber, M.; Kloppel, G.; Yoshimura, A.; Reindl, W.; Sipos, B.; Akira, S.; et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011, 19, 456–469. [Google Scholar] [CrossRef] [PubMed]
  125. Gui, Y.; Yeganeh, M.; Ramanathan, S.; Leblanc, C.; Pomerleau, V.; Ferbeyre, G.; Saucier, C.; Ilangumaran, S. SOCS1 controls liver regeneration by regulating HGF signaling in hepatocytes. J. Hepatol. 2011, 55, 1300–1308. [Google Scholar] [CrossRef] [PubMed]
  126. Yeganeh, M.; Gui, Y.; Kandhi, R.; Bobbala, D.; Tobelaim, W.S.; Saucier, C.; Yoshimura, A.; Ferbeyre, G.; Ramanathan, S.; Ilangumaran, S. Suppressor of cytokine signaling 1-dependent regulation of the expression and oncogenic functions of p21(CIP1/WAF1) in the liver. Oncogene 2016, 35, 4200–4211. [Google Scholar] [CrossRef] [PubMed]
  127. Yoshikawa, H.; Matsubara, K.; Qian, G.S.; Jackson, P.; Groopman, J.D.; Manning, J.E.; Harris, C.C.; Herman, J.G. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat. Genet. 2001, 28, 29–35. [Google Scholar] [CrossRef] [PubMed]
  128. Zhao, R.C.; Zhou, J.; He, J.Y.; Wei, Y.G.; Qin, Y.; Li, B. Aberrant promoter methylation of SOCS-1 gene may contribute to the pathogenesis of hepatocellular carcinoma: A meta-analysis. J. BUON 2016, 21, 142–151. [Google Scholar] [PubMed]
  129. Suzuki, M.; Shigematsu, H.; Shivapurkar, N.; Reddy, J.; Miyajima, K.; Takahashi, T.; Gazdar, A.F.; Frenkel, E.P. Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer. Cancer Lett. 2006, 242, 222–230. [Google Scholar] [CrossRef]
  130. Kobayashi, N.; Uemura, H.; Nagahama, K.; Okudela, K.; Furuya, M.; Ino, Y.; Ito, Y.; Hirano, H.; Inayama, Y.; Aoki, I.; et al. Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget 2012, 3, 1455–1471. [Google Scholar] [CrossRef]
  131. Chevrier, M.; Bobbala, D.; Villalobos-Hernandez, A.; Khan, M.G.; Ramanathan, S.; Saucier, C.; Ferbeyre, G.; Geha, S.; Ilangumaran, S. Expression of SOCS1 and the downstream targets of its putative tumor suppressor functions in prostate cancer. BMC Cancer 2017, 17, 157. [Google Scholar] [CrossRef] [PubMed]
  132. Villalobos-Hernandez, A.; Bobbala, D.; Kandhi, R.; Khan, M.G.; Mayhue, M.; Dubois, C.M.; Ferbeyre, G.; Saucier, C.; Ramanathan, S.; Ilangumaran, S. SOCS1 inhibits migration and invasion of prostate cancer cells, attenuates tumor growth and modulates the tumor stroma. Prostate Cancer Prostatic Dis. 2017, 20, 36–47. [Google Scholar] [CrossRef] [PubMed]
  133. Calabrese, V.; Mallette, F.A.; Deschenes-Simard, X.; Ramanathan, S.; Gagnon, J.; Moores, A.; Ilangumaran, S.; Ferbeyre, G. SOCS1 links cytokine signaling to p53 and senescence. Mol. Cell 2009, 36, 754–767. [Google Scholar] [CrossRef] [PubMed]
  134. Mallette, F.A.; Calabrese, V.; Ilangumaran, S.; Ferbeyre, G. SOCS1, a novel interaction partner of p53 controlling oncogene-induced senescence. Aging 2010, 2, 445–452. [Google Scholar] [CrossRef] [PubMed]
  135. Saint-Germain, E.; Mignacca, L.; Vernier, M.; Bobbala, D.; Ilangumaran, S.; Ferbeyre, G. SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes. Aging 2017, 9, 2137–2162. [Google Scholar] [CrossRef] [PubMed]
  136. Kong, X.; Feng, D.; Wang, H.; Hong, F.; Bertola, A.; Wang, F.S.; Gao, B. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012, 56, 1150–1159. [Google Scholar] [CrossRef] [PubMed]
  137. Bouamar, H.; Jiang, D.; Wang, L.; Lin, A.P.; Ortega, M.; Aguiar, R.C. MicroRNA 155 control of p53 activity is context dependent and mediated by Aicda and Socs1. Mol. Cell. Biol. 2015, 35, 1329–1340. [Google Scholar] [CrossRef] [PubMed]
  138. Cui, X.; Shan, X.; Qian, J.; Ji, Q.; Wang, L.; Wang, X.; Li, M.; Ding, H.; Liu, Q.; Chen, L.; et al. The suppressor of cytokine signaling SOCS1 promotes apoptosis of intestinal epithelial cells via p53 signaling in Crohn’s disease. Exper. Mol. Pathol. 2016, 101, 1–11. [Google Scholar] [CrossRef]
  139. Mallette, F.A.; Gaumont-Leclerc, M.F.; Ferbeyre, G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev. 2007, 21, 43–48. [Google Scholar] [CrossRef]
  140. Mallette, F.A.; Gaumont-Leclerc, M.F.; Huot, G.; Ferbeyre, G. Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence. J. Biol. Chem. 2007, 282, 34938–34944. [Google Scholar] [CrossRef]
  141. Mallette, F.A.; Moiseeva, O.; Calabrese, V.; Mao, B.; Gaumont-Leclerc, M.F.; Ferbeyre, G. Transcriptome analysis and tumor suppressor requirements of STAT5-induced senescence. Ann. N. Y. Acad. Sci. 2010, 1197, 142–151. [Google Scholar] [CrossRef] [PubMed]
  142. Barash, I. Stat5 in the mammary gland: Controlling normal development and cancer. J. Cell. Physiol. 2006, 209, 305–313. [Google Scholar] [CrossRef] [PubMed]
  143. Nevalainen, M.T.; Xie, J.; Torhorst, J.; Bubendorf, L.; Haas, P.; Kononen, J.; Sauter, G.; Rui, H. Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J. Clin. Oncol. 2004, 22, 2053–2060. [Google Scholar] [CrossRef]
  144. Peck, A.R.; Witkiewicz, A.K.; Liu, C.; Klimowicz, A.C.; Stringer, G.A.; Pequignot, E.; Freydin, B.; Yang, N.; Ertel, A.; Tran, T.H.; et al. Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. Breast Cancer Res. 2012, 14, R130. [Google Scholar] [CrossRef] [PubMed]
  145. Castro, P.; Giri, D.; Lamb, D.; Ittmann, M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 2003, 55, 30–38. [Google Scholar] [CrossRef] [PubMed]
  146. Gray-Schopfer, V.C.; Cheong, S.C.; Chong, H.; Chow, J.; Moss, T.; Abdel-Malek, Z.A.; Marais, R.; Wynford-Thomas, D.; Bennett, D.C. Cellular senescence in naevi and immortalisation in melanoma: A role for p16? Br. J. Cancer 2006, 95, 496–505. [Google Scholar] [CrossRef] [PubMed]
  147. Maldonado, J.L.; Timmerman, L.; Fridlyand, J.; Bastian, B.C. Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway. Am. J. Pathol. 2004, 164, 1783–1787. [Google Scholar] [CrossRef]
  148. Michaloglou, C.; Vredeveld, L.C.; Mooi, W.J.; Peeper, D.S. BRAF(E600) in benign and malignant human tumours. Oncogene 2008, 27, 877–895. [Google Scholar] [CrossRef]
  149. Michaloglou, C.; Vredeveld, L.C.; Soengas, M.S.; Denoyelle, C.; Kuilman, T.; van der Horst, C.M.; Majoor, D.M.; Shay, J.W.; Mooi, W.J.; Peeper, D.S. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005, 436, 720–724. [Google Scholar] [CrossRef] [PubMed]
  150. Vernier, M.; Bourdeau, V.; Gaumont-Leclerc, M.F.; Moiseeva, O.; Begin, V.; Saad, F.; Mes-Masson, A.M.; Ferbeyre, G. Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev. 2011, 25, 41–50. [Google Scholar] [CrossRef]
  151. Dorr, J.R.; Yu, Y.; Milanovic, M.; Beuster, G.; Zasada, C.; Dabritz, J.H.; Lisec, J.; Lenze, D.; Gerhardt, A.; Schleicher, K.; et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 2013, 501, 421–425. [Google Scholar] [CrossRef] [PubMed]
  152. Jing, H.; Kase, J.; Dorr, J.R.; Milanovic, M.; Lenze, D.; Grau, M.; Beuster, G.; Ji, S.; Reimann, M.; Lenz, P.; et al. Opposing roles of NF-kappaB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev. 2011, 25, 2137–2146. [Google Scholar] [CrossRef] [PubMed]
  153. Zardo, G.; Tiirikainen, M.I.; Hong, C.; Misra, A.; Feuerstein, B.G.; Volik, S.; Collins, C.C.; Lamborn, K.R.; Bollen, A.; Pinkel, D.; et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat. Genet. 2002, 32, 453–458. [Google Scholar] [CrossRef] [PubMed]
  154. Liu, T.C.; Lin, S.F.; Chang, J.G.; Yang, M.Y.; Hung, S.Y.; Chang, C.S. Epigenetic alteration of the SOCS1 gene in chronic myeloid leukaemia. Br. J. Haematol. 2003, 123, 654–661. [Google Scholar] [CrossRef] [PubMed]
  155. Chim, C.S.; Wong, K.Y.; Loong, F.; Srivastava, G. SOCS1 and SHP1 hypermethylation in mantle cell lymphoma and follicular lymphoma: Implications for epigenetic activation of the Jak/STAT pathway. Leukemia 2004, 18, 356–358. [Google Scholar] [CrossRef] [PubMed]
  156. Ekmekci, C.G.; Gutierrez, M.I.; Siraj, A.K.; Ozbek, U.; Bhatia, K. Aberrant methylation of multiple tumor suppressor genes in acute myeloid leukemia. Am. J. Hematol. 2004, 77, 233–240. [Google Scholar] [CrossRef]
  157. Sutherland, K.D.; Lindeman, G.J.; Choong, D.Y.; Wittlin, S.; Brentzell, L.; Phillips, W.; Campbell, I.G.; Visvader, J.E. Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Oncogene 2004, 23, 7726–7733. [Google Scholar] [CrossRef]
  158. Hatirnaz, O.; Ure, U.; Ar, C.; Akyerli, C.; Soysal, T.; Ferhanoglu, B.; Ozcelik, T.; Ozbek, U. The SOCS-1 gene methylation in chronic myeloid leukemia patients. Am. J. Hematol. 2007, 82, 729–730. [Google Scholar] [CrossRef]
  159. Jiang, S.; Zhang, H.W.; Lu, M.H.; He, X.H.; Li, Y.; Gu, H.; Liu, M.F.; Wang, E.D. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010, 70, 3119–3127. [Google Scholar] [CrossRef]
  160. Merkel, O.; Hamacher, F.; Griessl, R.; Grabner, L.; Schiefer, A.I.; Prutsch, N.; Baer, C.; Egger, G.; Schlederer, M.; Krenn, P.W.; et al. Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation. J. Pathol. 2015, 236, 445–456. [Google Scholar] [CrossRef]
  161. Zhao, X.D.; Zhang, W.; Liang, H.J.; Ji, W.Y. Overexpression of miR -155 promotes proliferation and invasion of human laryngeal squamous cell carcinoma via targeting SOCS1 and STAT3. PLoS ONE 2013, 8, e56395. [Google Scholar] [CrossRef]
  162. Saint-Germain, E.; Mignacca, L.; Huot, G.; Acevedo, M.; Moineau-Vallee, K.; Calabrese, V.; Bourdeau, V.; Rowell, M.C.; Ilangumaran, S.; Lessard, F.; et al. Phosphorylation of SOCS1 inhibits the SOCS1-p53 tumor suppressor axis. Cancer Res. 2019. [Google Scholar] [CrossRef] [PubMed]
  163. Guo, F.; Xu, Z.; Zhang, Y.; Jiang, P.; Huang, G.; Chen, S.; Lyu, X.; Zheng, P.; Zhao, X.; Zeng, Y.; et al. FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 2015, 6, 34606–34616. [Google Scholar] [CrossRef]
  164. Attia, Y.M.; Tawfiq, R.A.; Ali, A.A.; Elmazar, M.M. The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway. Sci. Rep. 2017, 7, 12502. [Google Scholar] [CrossRef] [PubMed]
  165. Sugase, T.; Takahashi, T.; Serada, S.; Fujimoto, M.; Hiramatsu, K.; Ohkawara, T.; Tanaka, K.; Miyazaki, Y.; Makino, T.; Kurokawa, Y.; et al. SOCS1 Gene Therapy Improves Radiosensitivity and Enhances Irradiation-Induced DNA Damage in Esophageal Squamous Cell Carcinoma. Cancer Res. 2017, 77, 6975–6986. [Google Scholar] [CrossRef] [PubMed]
  166. Sugase, T.; Takahashi, T.; Serada, S.; Fujimoto, M.; Ohkawara, T.; Hiramatsu, K.; Nishida, T.; Hirota, S.; Saito, Y.; Tanaka, K.; et al. SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling. Gastric Cancer 2018, 21, 968–976. [Google Scholar] [CrossRef] [PubMed]
  167. Yoneda, T.; Kunimura, N.; Kitagawa, K.; Fukui, Y.; Saito, H.; Narikiyo, K.; Ishiko, M.; Otsuki, N.; Nibu, K.I.; Fujisawa, M.; et al. Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo. Cancer Gene Ther. 2019. [Google Scholar] [CrossRef] [PubMed]
  168. de la Iglesia, N.; Konopka, G.; Puram, S.V.; Chan, J.A.; Bachoo, R.M.; You, M.J.; Levy, D.E.; Depinho, R.A.; Bonni, A. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 2008, 22, 449–462. [Google Scholar] [CrossRef] [PubMed]
  169. Sherry, M.M.; Reeves, A.; Wu, J.K.; Cochran, B.H. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 2009, 27, 2383–2392. [Google Scholar] [CrossRef]
  170. Pencik, J.; Schlederer, M.; Gruber, W.; Unger, C.; Walker, S.M.; Chalaris, A.; Marie, I.J.; Hassler, M.R.; Javaheri, T.; Aksoy, O.; et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat. Commun. 2015, 6, 7736. [Google Scholar] [CrossRef]
  171. Lessard, F.; Morin, F.; Ivanchuk, S.; Langlois, F.; Stefanovsky, V.; Rutka, J.; Moss, T. The ARF tumor suppressor controls ribosome biogenesis by regulating the RNA polymerase I transcription factor TTF-I. Mol. Cell 2010, 38, 539–550. [Google Scholar] [CrossRef] [PubMed]
  172. Sherr, C.J. The INK4a/ARF network in tumour suppression. Nat. Rev. Mol. Cell Biol. 2001, 2, 731–737. [Google Scholar] [CrossRef] [PubMed]
  173. Ko, A.; Han, S.Y.; Song, J. Regulatory Network of ARF in Cancer Development. Mol. Cell 2018, 41, 381–389. [Google Scholar] [CrossRef]
  174. Ferbeyre, G.; de Stanchina, E.; Lin, A.W.; Querido, E.; McCurrach, M.E.; Hannon, G.J.; Lowe, S.W. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol. Cell. Biol. 2002, 22, 3497–3508. [Google Scholar] [CrossRef] [PubMed]
  175. Pencik, J.; Wiebringhaus, R.; Susani, M.; Culig, Z.; Kenner, L. IL-6/STAT3/ARF: The guardians of senescence, cancer progression and metastasis in prostate cancer. Swiss Med. Wkly. 2015, 145, w14215. [Google Scholar] [CrossRef] [PubMed]
  176. Chin, Y.E.; Kitagawa, M.; Su, W.C.; You, Z.H.; Iwamoto, Y.; Fu, X.Y. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science 1996, 272, 719–722. [Google Scholar] [CrossRef] [PubMed]
  177. Bellido, T.; O’Brien, C.A.; Roberson, P.K.; Manolagas, S.C. Transcriptional activation of the p21(WAF1,CIP1,SDI1) gene by interleukin-6 type cytokines. A prerequisite for their pro-differentiating and anti-apoptotic effects on human osteoblastic cells. J. Biol. Chem. 1998, 273, 21137–21144. [Google Scholar] [CrossRef] [PubMed]
  178. Grabner, B.; Schramek, D.; Mueller, K.M.; Moll, H.P.; Svinka, J.; Hoffmann, T.; Bauer, E.; Blaas, L.; Hruschka, N.; Zboray, K.; et al. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat. Commun. 2015, 6, 6285. [Google Scholar] [CrossRef] [PubMed]
  179. Musteanu, M.; Blaas, L.; Mair, M.; Schlederer, M.; Bilban, M.; Tauber, S.; Esterbauer, H.; Mueller, M.; Casanova, E.; Kenner, L.; et al. Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology 2010, 138, 1003–1011. [Google Scholar] [CrossRef]
  180. Lee, J.; Kim, J.C.; Lee, S.E.; Quinley, C.; Kim, H.; Herdman, S.; Corr, M.; Raz, E. Signal transducer and activator of transcription 3 (STAT3) protein suppresses adenoma-to-carcinoma transition in Apcmin/+ mice via regulation of Snail-1 (SNAI) protein stability. J. Biol. Chem. 2012, 287, 18182–18189. [Google Scholar] [CrossRef]
  181. Couto, J.P.; Daly, L.; Almeida, A.; Knauf, J.A.; Fagin, J.A.; Sobrinho-Simoes, M.; Lima, J.; Maximo, V.; Soares, P.; Lyden, D.; et al. STAT3 negatively regulates thyroid tumorigenesis. Proc. Natl. Acad. Sci. USA 2012, 109, E2361–E2370. [Google Scholar] [CrossRef] [PubMed]
  182. Wang, H.; Lafdil, F.; Wang, L.; Park, O.; Yin, S.; Niu, J.; Miller, A.M.; Sun, Z.; Gao, B. Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. Am. J. Pathol. 2011, 179, 714–724. [Google Scholar] [CrossRef] [PubMed]
  183. Schneller, D.; Machat, G.; Sousek, A.; Proell, V.; van Zijl, F.; Zulehner, G.; Huber, H.; Mair, M.; Muellner, M.K.; Nijman, S.M.; et al. p19(ARF)/p14(ARF) controls oncogenic functions of signal transducer and activator of transcription 3 in hepatocellular carcinoma. Hepatology 2011, 54, 164–172. [Google Scholar] [CrossRef] [PubMed]
  184. Zhang, H.F.; Chen, Y.; Wu, C.; Wu, Z.Y.; Tweardy, D.J.; Alshareef, A.; Liao, L.D.; Xue, Y.J.; Wu, J.Y.; Chen, B.; et al. The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3beta in Esophageal Squamous Cell Carcinoma. Clin. Cancer Res. 2016, 22, 691–703. [Google Scholar] [CrossRef] [PubMed]
  185. Pectasides, E.; Egloff, A.M.; Sasaki, C.; Kountourakis, P.; Burtness, B.; Fountzilas, G.; Dafni, U.; Zaramboukas, T.; Rampias, T.; Rimm, D.; et al. Nuclear localization of signal transducer and activator of transcription 3 in head and neck squamous cell carcinoma is associated with a better prognosis. Clin. Cancer Res. 2010, 16, 2427–2434. [Google Scholar] [CrossRef]
  186. Gordziel, C.; Bratsch, J.; Moriggl, R.; Knosel, T.; Friedrich, K. Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma. Br. J. Cancer 2013, 109, 138–146. [Google Scholar] [CrossRef] [PubMed]
  187. Ettl, T.; Stiegler, C.; Zeitler, K.; Agaimy, A.; Zenk, J.; Reichert, T.E.; Gosau, M.; Kuhnel, T.; Brockhoff, G.; Schwarz, S. EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis. Hum. Pathol. 2012, 43, 921–931. [Google Scholar] [CrossRef] [PubMed]
  188. Sato, T.; Neilson, L.M.; Peck, A.R.; Liu, C.; Tran, T.H.; Witkiewicz, A.; Hyslop, T.; Nevalainen, M.T.; Sauter, G.; Rui, H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am. J. Cancer Res. 2011, 1, 347–355. [Google Scholar] [PubMed]
Figure 1. Map of somatic mutations detected in human Signal Transducer and Activator of Transcription (STAT)5A, STAT5B and STAT3 in patients with solid cancers. Individual missense mutations found in at least two patients (A), as well as all reported nonsense and frameshift mutations (B), are depicted. Numbers in each box represent the number of cases reported for each mutation. Data were mined from the Catalogue of Somatic Mutations In Cancer (COSMIC) database. ND, N-terminal domain; CCD, Coiled coil domain; DBD, DNA binding domain; LD, Linker domain; SH2, Src homology 2 domain; TAD, Transactivation domain.
Figure 1. Map of somatic mutations detected in human Signal Transducer and Activator of Transcription (STAT)5A, STAT5B and STAT3 in patients with solid cancers. Individual missense mutations found in at least two patients (A), as well as all reported nonsense and frameshift mutations (B), are depicted. Numbers in each box represent the number of cases reported for each mutation. Data were mined from the Catalogue of Somatic Mutations In Cancer (COSMIC) database. ND, N-terminal domain; CCD, Coiled coil domain; DBD, DNA binding domain; LD, Linker domain; SH2, Src homology 2 domain; TAD, Transactivation domain.
Cancers 11 01428 g001
Figure 2. Mechanisms of tumorigenic activity of STAT3 and STAT5 signaling in solid tumors.
Figure 2. Mechanisms of tumorigenic activity of STAT3 and STAT5 signaling in solid tumors.
Cancers 11 01428 g002
Figure 3. Tumor suppressor pathways acting on STAT3/5 activity (Protein Inhibitor of Activated STAT3 PIAS, miRNAs, E3 ligases, phosphatases) or activated by STAT3/5 transcriptional activity (Protein of alternative reading frame 19 (p19ARF) Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3), p53). Abbreviations: (PTPN2 (Tyrosine-protein phosphatase non-receptor type 2), PTPN9/MEG2 (Tyrosine-protein phosphatase non-receptor type 9), PTPN11/SHP2 (Tyrosine-protein phosphatase non-receptor type 11), PTPN6/SHP1 (Tyrosine-protein phosphatase non-receptor type 6) and TNF receptor associated factor 6 (TRAF6)).
Figure 3. Tumor suppressor pathways acting on STAT3/5 activity (Protein Inhibitor of Activated STAT3 PIAS, miRNAs, E3 ligases, phosphatases) or activated by STAT3/5 transcriptional activity (Protein of alternative reading frame 19 (p19ARF) Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3), p53). Abbreviations: (PTPN2 (Tyrosine-protein phosphatase non-receptor type 2), PTPN9/MEG2 (Tyrosine-protein phosphatase non-receptor type 9), PTPN11/SHP2 (Tyrosine-protein phosphatase non-receptor type 11), PTPN6/SHP1 (Tyrosine-protein phosphatase non-receptor type 6) and TNF receptor associated factor 6 (TRAF6)).
Cancers 11 01428 g003
Table 1. STAT3/5 activity and overall survival in major human solid tumors.
Table 1. STAT3/5 activity and overall survival in major human solid tumors.
Tumor TypeBiomarker/Type of StudyOverall SurvivalRef
NSCLCHigh p-STAT3/Meta-analysis of 9 studiesLog HR 0.67, 95% CI: 0.57–0.77, p < 0.0001[14]
NSCLCHigh p-STAT3/Cox regression multivariate analysisHR 2.45, 95% CI: 1.084–5.556, p = 0.031[15]
Lung cancerHigh p-STAT3/Meta-analysis of 13 studiesHR 1.23, 95% CI: 1.04–1.46, p = 0.02[16]
Pancreatic cancerHigh p-STAT3/Log-rank testNo association p > 0.05[17]
Liver cancer (HCC)High p-STAT3/Meta-analysis of 8 studiesHR 1.69, 95% CI: 1.07–2.31, p < 0.0001 3yr
HR 1.67, 95% CI: 1.18–2.15, p < 0.0001 5yr
[18]
Breast cancerHigh p-STAT3/Meta-analysis of 12 studiesNo association p > 0.05[19]
Breast cancer (ER+)High p-STAT3/Log-rank testNo association p > 0.05[20]
GBMHigh p-S727-STAT3/Cox regression multivariate analysisHR 1.797, 95% CI: 1.028–3.142, p = 0.040[21]
RCCHigh p-S727-STAT3/Cox regression multivariate analysisHR 3.32, 95% CI: 1.26–8.71, p = 0.014 10yr[22]
Colon cancerHigh p-STAT3/p-STAT5 ratio/Cox regression multivariate analysisHR 4.468, p = 0.043 5yr[10]
Colon cancerHigh p-STAT3/Log-rank testWorse overall survival, p < 0.001[23]
Colon cancerHigh p-STAT3/Cox regression multivariate analysisHR 1.61, 95% CI: 1.11–2.34, p = 0.015[24]
Breast cancerLow p-STAT5/Cox regression multivariate analysisHR 2.49, 95% CI: 1.23–5.05, p = 0.012 5yr[11]
Prostate cancerHigh nuclear STAT5A/B/Cox regression multivariate analysisHR 1.59, 95% CI: 1.04–2.44, p = 0.034[9]
ER+, estrogen receptor-positive; HCC, hepatocellular carcinoma; GBM, glioblastoma multiforme; NSCLC, non-small-cell lung carcinoma; HR, hazard ratio; RCC, renal cell carcinoma.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Back to TopTop