Roles of the transcription factors HNF6 and Sox9 in the initiation of metaplastic and neoplastic lesions of the pancreas
(2013)
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- Abstract
- Pancreatic ductal adenocarcinoma originates from acinar cells that undergo acinar-to-ductal metaplasia (ADM) and evolve to pancreatic intraepithelial neoplasia (PanIN), and eventually to invasive cancer. Ductal transcription factors are induced in ADM but the roles of these transcriptional regulators, in particular Hepatocyte Nuclear Factor (HNF) 6 and SRY-related HMG-box (Sox) 9, have not yet been investigated. Here we show that HNF6 and SOX9 are expressed in human and mouse ADM. Using in vitro and in vivo gain- and loss-of-function experiments, we demonstrate that both factors are essential for ADM induced by pancreatic duct ligation-mediated pancreatitis or by exposure to the carcinogen 9,10-dimethyl-1,2-benzanthracene. HNF6 and, to a lesser extent, Sox9 are required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity, and for activation of ductal genes in metaplastic acinar cells. SOX9, but not HNF6, is expressed in human and mouse PanIN lesions. Using in vitro and in vivo loss-of-function experiments, we show that Sox9 is required for development of PanIN from acinar cells harboring an oncogenic Kras mutation and exposed to an inflammatory stimulus. Sox9 stimulates expression of several metaplastic genes (cytokeratin 19, clusterin, ezrin) to promote ADM. It further stimulates the activity of the Erythroblastic leukemia viral oncogene homolog (ErbB) signaling pathway, which is required for initiation and progression of pancreatic ductal adenocarcinoma. Together, our findings demonstrate that HNF6 and Sox9 promote pancreatitisdriven ADM and are biomarkers of ADM. Also, Sox9 acts as an oncogene in pancreatic cancer by promoting tumor progression via stimulation of the ErbB signaling pathway.
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Grimont, A. (2013). Roles of the transcription factors HNF6 and Sox9 in the initiation of metaplastic and neoplastic lesions of the pancreas. https://hdl.handle.net/2078.5/202942