STAT3 can serve as a hit in the process of malignant transformation of primary cells

Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1a level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/ progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues. Signal transducers and activators of transcription (STAT) factors mediate the signaling downstream of cytokine and growth factor receptors. 1,2 Once activated by tyrosinephosphorylation by receptor-associated JAK kinases, STATs concentrate into the nucleus and regulate the expression of target genes. 3 STAT3 can be activated by a wide variety of cytokines and growth factors and by a number of oncogenes, 1 and is accordingly constitutively phosphorylated on tyrosine in many tumors that often become addicted to its activity. 1,2,4 Indeed, STAT3 is required for cell transformation downstream of v-Src and many other oncogenes, 4-6 and overexpression of a constitutively active mutant form can transform immortalized fibroblasts and epithelial cells. 7,8 Even though STAT3 is often referred to as an oncogene, only recently a naturally activating mutation has been found in human hepatocellular adenomas, 9 and its aberrant activity in tumors mostly occurs downstream of multiple activated pro-oncogenic pathways. Importantly, STAT3 is a key player in mediating inflammationdriven tumorigenesis, being constitutively activated by chronically high levels of the pro-inflammatory cytokine In tumors, STAT3 is known to enhance cell survival and proliferation and to promote immune escape and angiogenesis, invasion and metastasis. 11,12 In an effort to characterize pro-oncogenic functions of continuous, weak STAT3 activation, we have recently generated knock-in mi...

STAT3 negatively regulates thyroid tumorigenesis

“…Phospho-S727 STAT3 has been shown to localize in the mitochondria, where it positively regulates the activity of complex I/II of OXPHOS (26,56). In contrast, pY-STAT3 was shown to up-regulate glycolysis in fibroblasts and STAT3-dependent cancer cell lines (57,58). Given the hypoxic nature of tumors, we investigated whether STAT3 deficiency could alter the metabolic function of TCCs.…”

“…Given that a serinephosphorylated but tyrosine-mutant form of STAT3 was unable to rescue the STAT3 knockdown phenotype in our studies, the regulation of OXPHOS activity by mSTAT3 does not seem to be at play in our models. However, work in the laboratory of Valeria Poli has shown that transcripts encoding for mitochondrial proteins belonging to OXPHOS complexes were reduced in cells expressing constitutively activated pY-STAT3, which was associated with reduced complexes IV/V activity (57,58). Adding to the complexity of the roles of STAT3 in regulating metabolism, recent work showed that nuclear STAT3 can be tyrosine-phosphorylated by the dimeric M2 isoform of pyruvate kinase (PKM2), and together, they form a transcriptional activating complex participating in a PKM2/HIF1α-positive feedback loop (61,62).…”

Systemic Administration of a Cyclic Signal Transducer and Activator of Transcription 3 (STAT3) Decoy Oligonucleotide Inhibits Tumor Growth without Inducing Toxicological Effects

“…Approximately 95% of head and neck cancers overexpress STAT3 (19). Targeted deletion of STAT3 prevented epithelial cancers in skin cells (20), and the oncogenic role of STAT3 was shown by the ability of a constitutively active mutant to transform fibroblasts in vitro (7) and initiate tumor formation in vivo (21). Increased expression of activated STAT3 has been correlated with tumor stage and poor prognosis (7).…”

Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

“…Phosphorylated Stat3 translocates to the nucleus and activates genes involved in proliferation, survival, and mucosal defense (Bollrath et al, 2009;Pickert et al, 2009;Ernst et al, 2014). Mutations in STAT3 have been identified as susceptibility factors for inflammatory bowel disease (Bollrath et al, 2009;Anderson et al, 2011;Demaria et al, 2012), and in mice, upon DSSinduced colitis, epithelial Stat3 is required for mucosal wound healing (Pickert et al, 2009).…”