Up-regulation of c-MYC and SIRT1 expression correlates with malignant transformation in the serrated route to colorectal cancer

// Lydia Kriegl 1 , Michael Vieth 2 , Thomas Kirchner 1 , Antje Menssen 1 1 Department of Pathology, Ludwig-Maximilians-University (LMU), Munich. Germany 2 Department of Pathology, Klinikum Bayreuth, Bayreuth, Germany Correspondence: Antje Menssen, email: // Keywords : Serrated route, colorectal cancer, SIRT1, c-MYC, BRAF and KRAS mutation Received : August 20, 2012, Accepted : October 01, 2012, Published : October 03, 2012 Abstract Approximately 7.5% of all colorectal cancers are considered to originate from the alternative, serrated route. Here, we investigate the expression of the c-MYC oncogene and the SIRT1 protein deacetylase by immunohistochemical staining in subgroups of colorectal serrated lesions that were characterized by different molecular alterations. The expression of c-MYC and SIRT1 correlated with the presence of KRAS and BRAF mutations and high expression of c-MYC and SIRT1 was strongly associated with higher grades of malignancy. In contrast, in the majority of serrated lesions without KRAS or BRAF mutations, c-MYC and SIRT1 expression was not found increased. In this group only a subset of mostly high grade intraepithelial neoplasia and carcinoma was characterized by elevated c-MYC and SIRT1 expression. This was associated with nuclear localization of beta-catenin, indicating that Wnt pathway activation may confer transcriptional induction of c-MYC. In summary, we established a link between oncogenic K-Ras and B-Raf, suggesting post-transcriptional regulation of c-MYC through MAPK/ERK1/2 pathway activation, as well as for Wnt signalling to the activation of the c-MYC oncogene, and consequently of SIRT1 in the serrated route. The increasing expressions with higher grades of malignancy suggest crucial functions for c-MYC and SIRT1 in the progression of serrated lesions to colorectal cancer. These functions may include antagonizing of apoptosis and senescence, which are characteristic features of serrated lesions.