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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 5  |  Page : 67-73

Signal transducers and activators of transcription 3 function in lung cancer


1 Department of Cardiology, Tianjin Chest Hospital; Tianjin University of Traditional Chinese Medicine, Tianjin 300051, China
2 Department of Respiratory, Tianjin Chest Hospital, Tianjin 300051, China

Date of Web Publication30-Sep-2013

Correspondence Address:
Yue-Chuan Li
Department of Respiratory, Tianjin Chest Hospital, Tianjin 300051
China
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Source of Support: This research is supported by Technology major projects(2012ZX09103201-046), Conflict of Interest: None


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 > Abstract 

Constitutively activation of signal transducers and activators of transcription 3 (STAT3) proteins are involved in multiple aberrant signaling pathway-oncogenic pathways, including pathways regulating tumor cell survival. STAT3 is one of the second messengers in the Janus activated family kinases/STAT signaling pathway and is regulated by many different factors involving tumorigenesis. Given that the activation of STAT3 is observed in nearly 50% of Lung cancers and more and more researches regarding STAT3 in tumors, here in, we reviewed the contribution of STAT3 to lung cancer growth and progression and then the context in which positive and negative regulation of STAT activation leading to cell competition provides a mechanism for therapeutic intervention for specific cancers is discussed.

Keywords: Cell competition, epidermal growth factor receptor, lung cancer, signal transducers and activators of transcription 3


How to cite this article:
Li CJ, Li YC, Zhang DR, Pan JH. Signal transducers and activators of transcription 3 function in lung cancer. J Can Res Ther 2013;9, Suppl S1:67-73

How to cite this URL:
Li CJ, Li YC, Zhang DR, Pan JH. Signal transducers and activators of transcription 3 function in lung cancer. J Can Res Ther [serial online] 2013 [cited 2019 Nov 18];9:67-73. Available from: http://www.cancerjournal.net/text.asp?2013/9/5/67/119100


 > Introduction Top


Lung cancer is a lethal disease, which is being as a leading cause of cancer-related mortality world widely, with lung cancer caused 20% of all cancer-related deaths in Europe and 29% in the United States in 2004. [1] Lung tumors are routinely classified in two major histological subtypes: small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). The NSCLC, the most common type, is further divided into squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma. Adenocarcinoma has become the most prevalent subtype of NSCLC in recent decades. [2]

The signal transducers and activators of transcription 3 (STAT3), a potent transcription factor regulating cell growth, differentiation and cell death, is usually constitutively activated in a variety of malignancies and considered as an attractive drug target. It is indicated that STAT3 is activation in nearly 50% of lung cancers. Moreover, STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine (Tyr) kinases, like Janus activated family kinases (JAK) kinases. In addition, a specific kinase-driven pathway that has well-known significance in lung cancer is the epidermal growth factor receptor (EGFR) family signaling network. [3],[4],[5] Overexpression of EGFR has been observed in 40% to 80% of the NSCLC, EGFR and can regulate NSCLC growth and survival. And STAT3 is also regulated by the upstream EGFR signaling pathway. STAT3 activation in cells with activating EGFR mutations has been observed.

During recent years, it has been documented that STAT3 is regulated through direct approaches including decoy oligonucleotides, anti-sensor small interfering ribonucleic acid (siRNA) molecules or small molecule inhibitors, another approach would be to target the upstream kinases responsible for STAT3 activation to both positive and negative functions in cancer regulations.

In this review, we mainly discussed the roles of STAT proteins in the lung cancer. Moreover, we highlight the positive and negative regulations in cancer progression, which demonstrated the important implications of these molecules in tumorigenesis, growth and survival and possible applications for cancer therapeutics.


 > STAT3 in the Lung Cancer Top


In mammals, the STAT3 is a transcription factor, together with other six proteins: STAT1, STAT2, STAT4, STAT5A, STAT5B and STAT6, constitutes STAT family, which present a unique model of activation. [6] They make up a family of latent that traffic between the cytosol and the nucleus and mediate a number of cellular events, including proliferation, differentiation, apoptosis, cell survival, apoptosis, angiogenesis and immune activation, in response to cytokine and growth factor activation. Regarding to STAT3, it should be noted that this protein is the most often associated with tumorigenesis. Its essential oncogenic function involves the influence on pro-survival and pro-proliferative genes known to be crucial for tumor growth, invasiveness and cell survival. [7]

STAT3 has been known as an oncoprotein, which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. [8] STAT proteins are second messengers in the JAK/STAT signaling pathway. [9] And STAT activation - mainly STAT3 - is associated with JAK kinase, as well as non-receptor Tyr kinases (e.g., Src and Abl). This JAK/STAT pathway begins by the binding of a series of extracellular proteins, such as cytokines, growth factors, hormones and membrane receptors, which are the main factors regulating cell growth, the cell cycle, proliferation and development. Cytokine binding induces Tyr kinases JAKs (JAK family: JAK1, JAK2, JAK3 and Tyk2), become activated, leading to STAT proteins phosphorylation. Thus, STATs undergo dimerization and finally translocation to and retention in the nucleus, where they interact with members of the specific gene enhancers gamma activated site elements, acting as transcription factors to induce the transcription of target genes, commonly referred to as interferon (IFN) stimulated genes. [10] Constitutively activated STATs are involved in an aberrant JAK/STAT signaling pathway activation, which is important for transforming properties and tumorigenesis. [11]

Constitutive STAT3 activation contributes to the survival and proliferation of the lung, [12] breast, [13] colon, [14] prostate, [15] pancreas, kidney, skin cancers and osteosarcoma, [16] as well as leukemias [17] and lymphomas. [18] Notably, STAT3 activation has also been linked with metastasis of many of the same types of malignancies. STAT3 activation increases cancer cell migration and lung metastases. [19],[20]

The STAT3 contains a critical Tyr residue at the C-terminus (Tyr 705 for STAT3) which is phosphorylated during activation. Notably, unphosphorylated STAT (U-STAT) proteins can also regulate gene transcription. [21]

Lung cancer continues to be the leading form of cancer death in both men and women in the United States with an estimated 166,280 deaths attributed to lung cancer in 2008. NSCLC is the most common type. Approximately, 10%-40% of patients diagnosed with lung cancer report no history of tobacco smoking. Members of the STAT family of transcription factors are potential targets in lung cancer and other cancers. [22]


 > STAT3 and Inflammation in Cancer Top


Inflammation is commonly associated with lung tumors. In addition to direct prosurvival and anti-apoptotic functions, STAT3 activation leads to the expression of proinflammatory cytokines and chemokines, which have been shown to be important in establishing procarcinogenic inflammatory microenvironments. [23] These STAT3-dependent inflammatory conditions can arise as a result of infection, [24] stress [25] and exposure to ultra violet light [26] and carcinogenic substances such as those found in cigarettes, [27] contributing to the development of several cancer types. [28]

Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated STAT3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the STAT3 pathway by immune-mediated cytokines.

Indeed, tumor-associated macrophages (TAMs) constitute a major cell population in the breast tumor microenvironment (TME), promoting growth and metastasis of breast cancer. [29],[30] However, STAT3 plays an important role in this signal transmission. The EGFR/signal STAT3/Sox-2 paracrine signaling pathway between macrophages and mouse breast cancer cells that is required for macrophage-induced up regulation of Sox-2 and cancer stem cell (CSC) phenotypes in tumor cells, [31] this crosstalk was effectively blocked by the small molecule inhibitors AG1478 or CDDO-Im against EGFR and STAT3, respectively. Therefore, TAMs in breast CSC regulation and establishes a rationale for targeting the EGFR/Stat3/Sox-2 signaling pathway for CSC therapy. [32]

Besised, STATs conduct signals for a large family of cytokines, including the IFN family (IFNα/β; IFNγ), [33],[34] interleukins (IL). [35],[36] The pro-inflammatory cytokines may activate STAT and/or JAK proteins, which therefore influence pro-and anti-inflammatory phenotypes.

Cytokines like IL-6 have been demonstrated to modulate lung cancer cell growth and elevated levels of IL-6 have been shown to be an adverse prognostic factor for patients with lung cancer. The JAK/STAT pathway, have emerged as important factors in the modulation of cancer-associated inflammation. [12] STAT3 is activated in response to IL-6 to activate transcription of cell cycle-regulating proto-oncogenes and anti-apoptosis genes [37] to enhance cell survival. Mutations in the IL-6 receptor, gp130, can result in aberrant downstream signaling and STAT3 activation. Similar withIL-6, IL-1β also could regulate STAT3 in response to inflammation. [33],[38],[39],[40]

There is also evidence to support the role of enhanced IFN-inducible STAT3 phosphorylation in tumor regression. [41] IFN-α and IL-21 combination therapy activates STAT3, independent of STAT1 and STAT2, in CD8 + and in CD4 + T cells, which correlates with up regulated MHC class I expression. IFN-α-inducible STAT3 activation may trigger disease progression, presenting a risk factor to consider for IFN-based cancer therapies. [42]

The nuclear U-STAT proteinsU-STAT1 and U-STAT3 expression are increased in response to IFN-γ and IFN-β and IL-6, respectively. [21] Increased U-STAT3 expression up regulates M-Ras and c-Met oncogenes and could, therefore, play a role in oncogenesis. [43]

However, the activation of STAT proteins is regulated by suppressor of cytokine signaling protein, protein inhibitor of activated STATs (PIAS), Tyr phosphatases such as Srchomology 2 domain-containing tyrosinephosphatase (SHP-2) and by ubiquitination. [44],[45]


 > The Regulation of STAT3 Top


Most recently, in many studies focusing on inhibitions of JAK/STAT signaling, the nuclear and cytoplasmatic proteins, which are negative regulators of the activities of STAT proteins, have been mentioned. The specific inhibitors of STATs, called PIAS, can block deoxyribonucleic acid binding activity of STATs, therefore inhibiting STAT gene transcription. It has been documented in vivo that the key specific inhibitors STAT1 and STAT3 transcriptional activation are PIAS1 and PIAS3. [46] JAB (JAK-binding protein), SSI1 (STAT-induced STAT inhibitor 1) and cytokine inducible (CIS) (CIS SH2-containing protein) have been recognized as the most important of all inhibitors mentioned above. [9] Moreover, the small-molecule inhibitor of STAT3, BP-1-102, has been shown to inhibit STAT3 dimerization in multiple STAT3-dependent cancer cell lines, including MDA-MB-231 (breast carcinoma), DU145 (prostate carcinoma), NIH3T3/v-Src (transformed fibroblast), Panc-1 (pancreatic carcinoma) and A549 (lung adenocarcinoma), as well as inhibiting the growth of human breast and lung tumor xenografts when given orally or intravenously to graft-recipient mice. [47]

Despite many studies concerning the potential role of STAT3 in tumorigenesis, not all of the findings have been completely understood so far. However, many studies focused on human tumor and mammalian cell lines have confirmed the overexpression of non-receptor Tyr kinases and receptor kinases (IL-6/gp130 receptor family, platelet-derived growth factor receptor (PDGFR), EGFR, c-Src, c-Met and JAKs, BCR-Abl). [9],[48]

There is a balance between cell death and survival in living organisms. The ability of cells to sense their environment and decide to survive or die is dependent largely upon growth factors. EGF is a key growth factor regulating cell survival. Through its binding to the cell surface receptors, EGF activates an extensive network of signal transduction pathways that include activation of the PI3K/AKT, RAS/ERK and JAK/STAT pathways. [49] These pathways predominantly lead to activation or inhibition of transcription factors that regulate expression of both pro-and anti-apoptotic proteins effectively blocking the apoptotic pathway. In cancer, EGF signaling pathways are often dysfunctional and targeted therapies that block EGF signaling have been successful in treating cancers.

It is reported that nearly 50% of early stage NSCLC tumors have activated EGFR-STAT3 signaling with subsequent suppression of apoptosis, which demonstrated that EGFR signaling enhances STAT3 activity and STAT3 promotes survival in tumor specimens from NSCLC patients. [50] A recent paper found that 14% of patients with NSCLC in the United States have EGFR Tyr kinase domain mutations that are more common in never smokers, adenocarcinoma histology and in females. [51] The EGFR can be phosphorylated at different Tyr sites, leading to subsequent activation of different pathways. [52] And EGFR active site mutants are oncogenic. [53],[54] Two mutated EGFRs found in lung and other malignancies, EGFR-G719S and EGFR-LS58R, could transform Ba/F3 cells to IL-3-independent growth, in a ligand-independent manner, an activity associated with the transforming function of other mutated Tyr kinases. [55],[56]

Cell line and animal studies have shown that MAPK and STAT3 are important mediators of the EGFR signal in liver cells. In many human tumors and cell lines, a strong positive correlation between expression of EGF pathway - upstream in the signaling cascade for STATs - and phosphorylation (pSTAT3) has been observed. [57],[58] It is reported that pSTAT3 is an important factor during carcinogenesis and metastasis of lung carcinoma and the identification of pSTAT3 expression may behave as a sensor of upstream EGFR signaling. [57] pSTAT3 expression was found more often in patients with limited smoking history and it was identified a trend toward higher pSTAT3 expression in adenocarcinoma/bronchioloalveolar carcinoma tumors. [59] In the patient cohort consisting mainly of stage I tumors, expression of pSTAT3 had no apparent influence on prognosis following surgery. In addition, many reports suggest that mutant EGFR proteins may selectively enhance the influence of PI3K/AKT and JAK/STAT on IL-6. [60],[61],[62]

There are also several strategies that directly target STAT protein expression. These include siRNA to block STAT protein expression, [63],[64] small-molecule inhibitors that prevent STAT dimerization [65] and oligonucleotides that compete for STAT binding. [66],[67]

The well-known oncomiR-miR-21 was previously reported oncogenic activity in lung cancer. [68],[69] Tumor secreted miR-9 promotes endothelial cell migration and tumor angiogenesis in vivo. MiR-9 prominently triggers JAK-STAT activities and that inhibition of both JAK1 and JAK2 is sufficient to abrogate the effects. [70] The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK and targeting of the STAT3/miR-92a axis may be helpful for cancer treatment.

MiR-135b suppressed T-helper 2 master regulators STAT6 and GATA3 and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells. [71] Moreover, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, revealing the contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment. [72],[73]

Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs control diverse aspects of cell function, including immune regulation. [74] The type-2-skewing TME induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy. [72],[75]

Constitutive activation of STAT3 and STAT5 is a common event in many hematological malignancies, which is due to the persistent presence of phosphorylated STAT proteins on chromatin. Heterochromatin plays a role in chromosomal compaction and transcriptional silencing and is emerging as a mechanism of tumor suppression. It is demonstrated that unphosphorylated human STAT5A functions as a tumor suppressor capable of repressing multiple oncogenes via heterochromatin formation. [76] Unphosphorylated STAT5A binds to heterochromatin protein 1α (HP1α) and stabilizes heterochromatin. Expressing unphosphorylated STAT5A or HP1α inhibits colon cancer growth in mouse xenograft models. Transcriptome profiling shows that expressing an unphosphorylatable STAT5A has similar effects to overexpressing HP1α in global gene expression. Notably, Hu et al. [76] found that the majority of the genes commonly repressed by unphosphorylated STAT5A and HP1α have been implicated in cancer development. Strikingly, down-regulation, somatic mutations and deletions of STAT5 genes are found in certain human cancers, which demonstrated that unphosphorylated STAT5A may epigenetically suppress tumor growth by promoting heterochromatin formation. Contrary to the other known tumor suppressors, unphosphorylated STAT5A and HP1α may represent a unique class of tumor suppressors that are capable of, in addition to protecting genome stability, suppressing transcription of multiple cancer-promoting genes. This finding should lead to unique therapeutic options for treating human cancers.

Interestingly, it has been reported that unphosphorylated STAT1 and STAT3 regulate expression of target genes that are distinct from those controlled by their canonical pathways. It remains to be determined whether unphosphorylated STAT1 and STAT3 also share transcriptional targets with HP1α and whether they promote heterochromatin formation.


 > Jekyll and Hyde in Cancer Progression Top


The results of many studies have confirmed that the activation of the JAK/STAT pathway in mammalian cells is temporary and this activation may be regulated both in a positive and a negative manner. Regarding the role of STATs, it's claimed that STAT1 and STAT3 appear to act in opposite manner in tumorigenesis. [77] They either act directly, through transcriptional regulation of target genes, or indirectly via modulation of angiogenesis in tumor cells or by influencing the anti-tumor immune response. STAT3 and STAT5 are considered powerful proto-oncogenes, whereas it should be stressed that STAT1 is emerging as an important negative regulator of tumor formation and metastasis, as well as a modulator of tumor immunosurveillance. [78] It is suggested that a specific balance exists between activities of STAT1 and STAT3 in tumor cell.

Interestingly, STAT3 has both tumor suppressing and tumor promoting properties. Immunohistochemistry analysis of human lung cancer tissues revealed an increase in STAT3 activation at the invading edge of early-stage tumors, whereas STAT3 activation in A549 lung adenocarcinomic epithelial cells is associated with an upregulation in genes regulating cell migration and angiogenesis. [79] In addition, STAT3 up-regulation correlates with a poor prognosis. Similarly, recent studies have shown that STAT3 is the direct transcriptional regulator of β-catenin in breast cancer. STAT3 and β-catenin may cooperate together via modulating the upstream of Wnt canonical pathway, exerting their oncogenic effects. Constitutive STAT3 activation downregulates the expression of a lipid raft protein, Caveolin-1, in human breast cancer [20] and upregulates the expression of proangiogenic genes: Vascular endothelial growth factor, basic fibroblast growth factor and matrix metalloproteinase-2 in human melanoma. [19] The expression of STAT3αC in a rat fibroblast cell line transformed the cells and induced tumor formation in nude mice. [80] The generation of gene targeted mice allowed further insights into the function of STAT3 and established STAT3 as an important tumor promoter.

However, more recent studies using several cancer cell types suggest that the expression of truncated STAT3β can inhibit tumor growth, given that STAT3β, which lacks a serine phosphorylation site and transactivation domain, can compete with full-length STAT3α to downregulate transcriptional activation. Ecker et al. demonstrated that STAT3αC blocks c-myc induced transformation in primary murine fibroblasts, revealing that a constitutive active version of STAT3α (STAT3αC) may also suppress transformation. [81]


 > Cell Competition Top


Cell competition is a short-range elimination of slow-dividing cells through apoptosis from a faster growing population, which regulates organ size and shares properties with the early stages of cancer. There are two different context-dependent cell competition phenotypes. In "classical" cell competition, mutant cells survived when surrounded by cells with the same genotype, whereas they are eliminated when surrounded by wild type (wt) cells. Subsequently, wt cells replenish the tissue by compensatory proliferation. Thus induce a reduction of fitness leading to cell competition and intrinsic tumor suppression. However, the supercompetitor cells do not induce apoptosis when surrounded by cells with the same genotype, whereas they can grow by inducing the surrounding wt cells death. Winner cell growth is up-regulated by compensatory proliferation, through the secretion of Dpp, Wg, Hh and Unpaired from dying cells, or the non-cell autonomous down-regulation of Hippo pathway induced by dying cells. [82]

A general feature of cancer growth is the cellular competition for available nutrients. The JAK-STAT pathway has been involved previously in the regulation of growth and tissue size. [83],[84] It is reported that modulating JAK-STAT pathway activity levels also regulates competitor status. [85] Cells lacking STAT become losers that are killed neighboring wild-type cells through apoptosis. On the contrary, cells with hyper-activated STAT become supercompetitors that kill losers located at a distance in a manner that is dependent on hid but independent of Myc, Hippo pathway, Wingless signaling and ribosome biogenesis. [85]

As hyper-activated STATs are causal to tumorigenesis and stem cell niche occupancy, have therapeutic implications for cancer and regenerative medicine.


 > Summary Top


Viewed altogether, the STAT3 transcription factor is phosphorylated and activated by the JAK/STAT signaling pathway, function normally in cell growth, differentiation and cell death. While undergoing abnormal constitutively activation, leads to tumor growth, cell migration and angiogenesis. STAT3 activation may be a molecular marker in lung cancer that predicts tumor dependency on upstream EGFR and relative resistance to cytotoxic chemotherapy via regulation of survival pathways, however more confirmations of these hypotheses will require in prospective testing in clinical trials. Most researches indicated that the activation of STAT3 enhances tumorigenesis, while recently studies clarified the opposite functions of repressing tumor growth. We highlight that the cell competition may be the important contribution that activation of STATs has to tumorigenesis, whether in certain cancers this relates to promoting progression and metastasis or in other circumstances, to limiting tumor growth.





This research is supported by Technology major projects (2012ZX09103201-046).

 
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