Expression of MUC17 Is Regulated by HIF1a-Mediated
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MUC17 is a type 1 membrane-bound glycoprotein that is mainly expressed in the digestive tract. Recent studies havedemonstrated that the aberrant overexpression of MUC17 is correlated with the malignant potential of pancreatic ductaladenocarcinomas (PDACs); however, the exact regulatory mechanism of MUC17 expression has yet to be identified. Here,we provide the first report of the MUC17 regulatory mechanism under hypoxia, an essential feature of the tumormicroenvironment and a driving force of cancer progression. Our data revealed that MUC17 was significantly induced byhypoxic stimulation through a hypoxia-inducible factor 1a (HIF1a)-dependent pathway in some pancreatic cancer cells (e.g.,AsPC1), whereas other pancreatic cancer cells (e.g., BxPC3) exhibited little response to hypoxia. Interestingly, these lowresponsivecells have highly methylated CpG motifs within the hypoxia responsive element (HRE, 59-RCGTG-39), a bindingsite for HIF1a. Thus, we investigated the demethylation effects of CpG at HRE on the hypoxic induction of MUC17.Treatment of low-responsive cells with 5-aza-29-deoxycytidine followed by additional hypoxic incubation resulted in therestoration of hypoxic MUC17 induction. Furthermore, DNA methylation of HRE in pancreatic tissues from patients withPDACs showed higher hypomethylation status as compared to those from non-cancerous tissues, and hypomethylation wasalso correlated with MUC17 mRNA expression. Taken together, these findings suggested that the HIF1a-mediated hypoxicsignal pathway contributes to MUC17 expression, and DNA methylation of HRE could be a determinant of the hypoxicinducibility of MUC17 in pancreatic cancer cells.
- Public Library of Scienceの論文
- 2012-09-10
Public Library of Science | 論文
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