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.
Highlights
Colorectal cancer is the third most common cancer in the world and is one of the leading causes of cancer-related deaths [1]
BRAF mutation was found in 73 cases comprising 20 hyperplastic polyps, 24 sessile serrated adenomas without intraepithelial neoplasia, 2 sessile serrated adenomas with low grade intraepithelial neoplasia, 8 sessile serrated adenomas with high grade intraepithelial neoplasia, 10 traditional serrated adenomas with low grade intraepithelial neoplasia, 1 traditional serrated adenoma with high grade intraepithelial neoplasia and 8 invasive serrated adenocarcinomas
KRAS mutation was present in 22 cases including 1 hyperplastic polyp, 1 sessile serrated adenoma without intraepithelial neoplasia, 2 sessile serrated adenomas with high grade intraepithelial neoplasia, 9 traditional serrated adenomas with low grade intraepithelial neoplasia, 1 traditional serrated adenoma with high grade intraepithelial neoplasia and 8 invasive serrated adenocarcinomas
Summary
Colorectal cancer is the third most common cancer in the world and is one of the leading causes of cancer-related deaths [1]. Malignant transformation in the classical adenoma – carcinoma sequence is crucially associated with the activation of the Wnt/beta-catenin signaling pathway which leads to the transcriptional induction of the c-MYC oncogene [2]. Besides the classical adenoma – carcinoma sequence, strong evidence for an alternative serrated pathway in the development of colorectal cancer has emerged in recent years [3, 4]. In contrast to the classical adenoma–carcinoma sequence, deregulation of the Wnt/beta-catenin pathway is rarely observed, whereas mutations of BRAF, and less frequently KRAS have been shown to be the initiating events in the serrated route to colorectal cancer [5,6,7,8]. Besides lesions with mutant KRAS or BRAF, a third subset exists which does not display any known aberrant oncogene activation
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