Villin Expression Is Frequently Lost in Poorly Differentiated Colon Cancer

被引:32
作者
Arango, Diego [2 ,3 ]
Al-Obaidi, Sheren
Williams, David S. [4 ]
Dopeso, Higinio [2 ]
Mazzolini, Rocco [2 ]
Corner, Georgia
Byun, Do-Sun [5 ]
Carr, Azadeh A. [6 ]
Murone, Carmel
Toegel, Lars
Zeps, Nikolajs [7 ]
Aaltonen, Lauri A. [8 ]
Iacopetta, Barry [7 ]
Mariadason, John M. [1 ,5 ]
机构
[1] Ludwig Inst Canc Res, Austin Branch, Austin Hlth, Heidelberg, Vic 3084, Australia
[2] Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Mol Biol & Biochem Res Ctr Nanomed, Res Inst, E-08193 Barcelona, Spain
[3] CIBER Bioingn Biomat Nanomed CIBER BBN, Zaragoza, Spain
[4] Austin Hlth, Dept Pathol, Melbourne, Vic, Australia
[5] Montefiore Med Ctr, Dept Oncol, Albert Einstein Coll Med, Bronx, NY 10467 USA
[6] Montefiore Med Ctr, Albert Einstein Canc Ctr, Dept Surg, Bronx, NY 10467 USA
[7] Univ Western Australia, Sch Surg, Perth, WA 6009, Australia
[8] Univ Helsinki, Dept Med Genet, Biomedicum Helsinki, Helsinki, Finland
基金
澳大利亚研究理事会;
关键词
TUMOR MICROSATELLITE-INSTABILITY; ISLAND METHYLATOR PHENOTYPE; COLORECTAL-CANCER; GENE-EXPRESSION; CELL-LINES; PROGNOSTIC-SIGNIFICANCE; ADJUVANT CHEMOTHERAPY; INTESTINAL-CELLS; CDX1; EXPRESSION; F-ACTIN;
D O I
10.1016/j.ajpath.2012.01.006
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Colorectal cancers (CRCs) are classified as having microsatellite instability (MSI) or chromosomal instability (CIN); herein termed inicrosatellite stable (MSS). MSI colon cancers frequently display a poorly differentiated histology for which the molecular basis is not well understood. Gene expression and immunohistochemical 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. (Am J Pathol 2012, 180:1509-1521; DOI: 10.1016/j.ajpath.2012.01.006)
引用
收藏
页码:1509 / 1521
页数:13
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