Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt–β-catenin–mediated intestinal tumor growth and regeneration

Abstract

Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-β-catenin pathway in the intestinal epithelium. Because Wnt-β-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-β-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer.

Chronic inflammation and the development of malignancy in the GI tract

“…Secondly, in AOM-related tumor models tumors with increased size and proliferation are seen in the presence of epithelial cells with increased STAT3 activation (i.e., cells with a gp130 Y757F mutation that prevents SOCS3 activation or with SOCS3 deficiency) (39). This finding is mirrored in the Apc min/+ tumor model in that Apc min/+ mice with mutated gp130 that cannot bind STAT3 and thus manifest reduced STAT3 activation, exhibit a decreased number and size of tumors as well as reduced early stage tumor formation; reciprocally, Apc min mice with gp130 that cannot bind SOCS3 and thus manifests increased STAT3 signaling, exhibit increased tumor formation (40). Taken together, these data provide more or less definitive evidence that STAT3 activation plays a necessary and sufficient role in the 2 nd Stage of inflammation associated epithelial cell tumor formation.…”

“…Taken together, these data provide more or less definitive evidence that STAT3 activation plays a necessary and sufficient role in the 2 nd Stage of inflammation associated epithelial cell tumor formation. Additional studies showing that Apc min/+ mice with epithelial cell-specific decreased STAT3 activity manifest decreased tumor formation indicate that the STAT3 signaling occurring in epithelial cells is the critical locus of tumor-inducing STAT3 activity (39, 40). …”

“…With respect to the down-stream oncogenic effects of STAT3 signaling, it was shown that STAT3 mutations causing decreased STAT3 activation do not necessarily impact Wnt signaling and β-catenin nuclear localization(40). This indicates that STAT3 signaling effects do not act via dysregulation of Wnt signaling and the latters pro-oncogenic effects are in reality 1 st Stage proneoplastic effects that are likely facilitated or aggravated by subsequent STAT3 signaling abnormalities.…”

“…This indicates that STAT3 signaling effects do not act via dysregulation of Wnt signaling and the latters pro-oncogenic effects are in reality 1 st Stage proneoplastic effects that are likely facilitated or aggravated by subsequent STAT3 signaling abnormalities. In the as yet limited studies exploring the neoplastic effects of STAT3 signaling, it has been shown that Apc min/+ mice with epithelial cell-specific inactivation of STAT3 display decreased abundance of cell cycle inhibitors p16 and p21 and, concomitantly, decreased expression of the polycomb group protein Bim-1, a protein that represses p16 and p21 (40). Moreover, evidence was obtained that STAT3 transactivates the Bmi-1 gene.…”

Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis

“…Signal transducer and activator of transcription 3 (STAT3) remains inactive in normal cells until activated by various cytokines and growth factors, such as IL-6 and EGF family members. However, STAT3 is often detected to be continuously activated in cancer cells, and several STAT3 knockout mouse models revealed that STAT3 is a critical oncogenic transcription factor for tumorigenesis in skin [21], intestine [22], and liver [23]. A suppressor of cytokine signaling 3 (SOCS3) is involved in a negative feedback mechanism that turns off the activation of STAT3 [24].…”