Abstract
Abstract Colorectal cancers are classified as having chromosomal instability (CIN) or microsatellite instability (MSI). MSI colon cancers frequently display poorly differentiated histology the molecular basis of which is not well understood. Gene expression profiling of CIN and MSI colon cancer cell lines and tumours revealed significant downregulation of the intestinal-specific cytoskeletal protein villin, in MSI tumours, with complete absence observed in 62% and 17% of MSI cell lines and primary tumours, respectively. Investigation of 577 colon cancers demonstrated loss of villin expression was linked to poorly differentiated histology in MSI and MSS (microsatellite stable) tumours. Furthermore, mislocalization of villin away from the membrane was prognostic for poorer outcome in MSS patients. Loss of villin expression was not due to coding sequence mutations, epigenetic inactivation, or promoter mutation. Conversely, villin promoter activity reflected endogenous villin expression, suggesting villin loss is transcriptionally mediated. A screen of gut-specific transcription factors revealed a significant correlation between expression of villin and the homeobox transcription factor, Cdx-1. Cdx-1 overexpression induced villin promoter activity, Cdx-1 knockdown downregulated endogenous villin expression, and deletion of a key Cdx binding site within the villin promoter attenuated promoter activity. Loss of Cdx-1 expression was associated with Cdx-1 promoter methylation. These findings demonstrate that loss of villin expression as a result of Cdx-1-dependent transcriptional deregulation is a feature of poorly differentiated colon cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4316. doi:1538-7445.AM2012-4316
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