title: Up-regulation of c-MYC and SIRT1 expression correlates with malignant transformation in the serrated route to colorectal cancer.
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.
authors.affiliation: Department of Pathology, Ludwig-Maximilians-University (LMU), Munich. Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kriegl
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Antje
authors.initials: A
authors.lastname: Menssen
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D003111:Colonic Polyps / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D056564:Sirtuin 1 / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins