Wael M. Abdel-Rahman, Johanna E Lotsari-Salomaa, Sippy Kaur, Anni Niskakoski, Sakari Knuutila, Heikki Järvinen, Jukka-Pekka Mecklin and Päivi Peltomäki
Department of Medical Laboratory Sciences, College of Health Sciences and SIMR, University of Sharjah, Sharjah, United Arab Emirates
A common initial step in colon cancer development is loss of APC tumor suppressor gene leading to constitutive activation of Wnt signaling. The aim of this work was to dissect the carcinogenic mechanisms of the rare colon tumors which do not show this feature using a representative cell line "RKO". MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray study of RKO vs. colon cancer lines with active Wnt signaling revealed 611 differentially expressed genes (399 up- and 212 down-regulated). The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected target genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) in primary tumors confirmed that they were differentially expressed in clinical specimens. Selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. This study identified novel target genes in colorectal carcinogenesis and confirmed the role of many others; such information would be useful to develop personalized tumor profiling.