Abstract
Although the biological role of KRAS is clearly established in carcinogenesis, the molecular mechanisms underlying this phenomenon are not completely understood. In this study, we provide evidence of a novel signaling network regulated by the transcription factor GLI1 mediating KRAS-induced carcinogenesis. Using pancreatic cancer (a disease with high prevalence of KRAS mutations) as a model, we show that loss of GLI1 blocks the progression of KRAS-induced pancreatic preneoplastic lesions in mice with pancreas-specific Cre-activated oncogenic mutant kras. Mice lacking GLI1 develop only low-grade lesions at low frequency, and in most cases, the pancreata are histologically normal. Further characterization of the phenotype showed a decrease in the activation of STAT3 in pancreatic preneoplastic lesions; STAT3 is a transcription factor required for the development of premalignant lesions and their progression into pancreatic cancer. Analysis of the mechanisms revealed a key role for GLI1 in maintaining the levels of activated STAT3 through the modulation of IL-6 signaling. GLI1 binds to the IL-6 mouse promoter and regulates the activity and expression of this cytokine. This newly identified GLI1/IL-6 axis is active in fibroblasts, a known source of IL-6 in the tumor microenvironment. Sonic hedgehog induces GLI1 binding to the IL-6 promoter and increases IL-6 expression in fibroblasts in a paracrine manner. Finally, we demonstrate that mutant KRAS initiates this cascade by inducing the expression of Sonic hedgehog in cancer cells. Collectively, these results define a novel role for GLI1 in carcinogenesis acting as a downstream effector of oncogenic KRAS in the tumor microenvironment.
Highlights
KRAS is a known oncogene driving transformation in multiple tissues
We initially sought to evaluate the pancreata of GKO mice in detail over an extended period of time to determine whether subtle developmental defects are present in the background of the colony in the absence of krasG12D, which could lead to an error in interpreting the results of our experiments
Given the high frequency of oncogenic KRAS mutations in preneoplastic lesions and the recapitulation of the carcinogenic process in mouse models with an endogenous oncogenic kras allele, activation of this GTPase is believed to be the crucial step in the initiation of pancreatic tumors (38)
Summary
KRAS is a known oncogene driving transformation in multiple tissues. Results: We demonstrate a role for the transcription factor GLI1 in KRAS-induced transformation through regulation of the IL-6/STAT3 axis in the tumor microenvironment. We demonstrate that mutant KRAS initiates this cascade by inducing the expression of Sonic hedgehog in cancer cells These results define a novel role for GLI1 in carcinogenesis acting as a downstream effector of oncogenic KRAS in the tumor microenvironment. The biological significance of these findings and the molecular mechanisms mediating this phenomenon remain elusive To address these issues, we used the well established Lox-Stop-Lox (LSL)2-krasG12D mouse crossed with the pancreas-specific p48-Cre mouse model of pancreatic cancer (referred to as KC mice). Further analysis of the mechanism underlying this phenomenon shows that GLI1 regulates activation of STAT3 through modulation of IL-6 expression and promoter activity in pancreatic fibroblasts Together, these findings define a novel signaling network in the tumor microenvironment required by KRAS to induce transformation that utilizes GLI1 as its central mediator
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