Abstract 4094: Pancreatic cancers epigenetically silence ZFHX1B, hypomethylate and overexpress miR-200a/−200b, in association with elevated circulating miR-200a and miR-200b levels

Aberrant DNA methylation and miRNA expression play important roles in the pathogenesis of pancreatic cancer. While interrogating differentially methylated CpG islands in pancreatic cancer we identified two members of miR-200 family, miR-200a and miR-200b that were hypomethylated and overexpressed in pancreatic cancer. We also identified prevalent hypermethylation and silencing of one of their downstream targets, ZFHX1B (SIP1, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition. In a panel of 23 pancreatic cell lines we observed a reciprocal correlation between miR-200, ZFHX1B and E-cadherin expression with pancreatic cancer associated fibroblasts showing the opposite expression pattern to most pancreatic cancers. In Panc-1cells, which express ZFHX1B, have low E-cadherin expression and do not express miR-200a or miR-200b, exogenous expression of miR-200a and miR-200b down regulated ZFHX1B mRNA and increased E-cadherin expression. However, most pancreatic cancers express miR-200a and miR-200b, but this expression does not affect ZFHX1B expression as the ZFHX1B promoter is silenced by hypermethylation, and in these cancers E-cadherin is generally expressed at or above normal levels. Both miR-200a and miR-200b were significantly elevated in the sera of pancreatic cancer and chronic pancreatitis patients compared to healthy controls (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4094.