No abstract

No abstract

Colorectal cancers (CRCs) are classified as having microsatellite instability (MSI) or chromosomal instability (CIN); herein termed microsatellite stable (MSS). MSI colon cancers frequently display a poorly differentiated histology for which the molecular basis is not well understood. Gene expression and immuno-histochemical profiling of MSS and MSI CRC cell lines and tumors revealed significant down-regulation of the intestinal-specific cytoskeletal protein villin in MSI colon cancer, with complete absence in 62% and 17% of MSI cell lines and tumors, respectively. Investigation of 577 CRCs linked loss of villin expression to poorly differentiated histology in MSI and MSS tumors. Furthermore, mislocalization of villin 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, in transient transfection assays villin promoter activity reflected endogenous villin expression, suggesting transcriptional control. 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 down-regulated endogenous villin expression, and deletion of a key Cdx-binding site within the villin promoter attenuated promoter activity. Loss of Cdx-1 expression in CRC lines was associated with Cdx-1 promoter methylation. These findings demonstrate that loss of villin expression due to Cdx-1 loss is a feature of poorly differentiated CRCs. Europe PMC Funders GroupAuthor Manuscript Am J Pathol. Author manuscript; available in PMC 2017 May 11. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsColorectal cancer (CRC) can be broadly classified as those displaying microsatellite instability (MSI) or chromosomal instability (CIN); herein referred to as microsatellite stable (MSS).1 MSI colon cancers can be further separated into familial (Lynch syndrome) or sporadic MSI. Patients with Lynch syndrome have inherited mutations in one of six DNA mismatch repair genes, although mutations in MLH1 and MSH2 account for the majority (∼90%) of cases.1,2 In Lynch syndrome, colonic tumors typically arise in the fourth decade of life, following loss of heterozygosity of the wild-type allele.1 In comparison, sporadic MSI is driven largely by epigenetic silencing of the MLH1 locus with significantly later tumor onset.3 Inactivation of DNA mismatch repair genes results in acquisition of a mutator phenotype, which in turn drives tumorigenesis through mutation of key oncogenic and tumor suppressor signaling pathways including Wnt, Ras/BRAF, transforming growth factor-β (TGF-β), and PI3K.Several cytogenetic and epigenetic differences exist between MSS/CIN and MSI tumors. In particular, MSS/CIN tumors display gains and losses of large chromosomal regions and multiple chromosomal rearrangements, whereas MSI tumors are largely diploid. Conv...

No abstract