Cullin-1 and -2 Protein Expression in Colorectal Cancer: Correlation with Clinicopathological Variables.

Abstract

The cullin (CUL) family of proteins is involved in the ubiquitin/mediated degradation of proteins, regulating cell proliferation, cell-cycle control, migration, invasion and metastasis in the process of tumor progression. The aim of the present study was to examine if there is any correlation between the immunohistochemical (IHC) expression of Cullin-1 and -2 proteins in colorectal cancer tissue specimens with several clinicopathological variables. Between January 2012 and December 2014, 96 consecutive adenocarcinoma patients were submitted to oncological colectomy, as the first therapeutic option, with a curative intent. CUL-1 and -2 protein expression was examined with IHC on paraffin-embedded tissue sections. CUL-1 and -2 protein positivity, was correlated with patients' age, gender, stage, histological grade, proliferative capacity (Ki-67 labeling index) and mutant p53 protein expression. The positivity for CUL-1, CUL-2, mutant p53 protein and Ki-67 index, was determined by the percentage of their IHC expression in the total number of cancer cells. Choosing as a cut-off point for CUL-1 positivity the 10%, a statistically significant relationship of the expression of the mutant p53 protein (p=0.04) and the co-expression of CUL-2 (p=0.003) were noticed. By setting the cut-off limit for CUL-2 expression to 10%, no statistically significant differences were observed between its expression and the examined clinicopathological variables. However, by increasing the cut-off limit for CUL-2 expression to 30%, a statistically significant correlation of its expression to the mutated p53 protein was noticed (p=0.047). Co-expression of CUL-1 and -2 in more than 10%, significantly correlated to the coexistence of adenomatous polyps along the large bowel (p=0.0329). Multivariate analysis of CUL-1 and -2 co-expression in more than 10% disclosed their expression as an independent factor for adenomatous polyps development in the large bowel (p=0.035, RR=2.1). CUL-1 overexpression may happen early in the process of carcinogenesis mainly affecting the vulnerable p53(+) large bowel cells, arresting them in the G1 phase of cell-cycle, while it may also induce the expression of CUL-2. Co-expression of CUL-1 and CUL-2, in the arrested (in G1 phase) large bowel cells, promotes carcinogenesis up to adenomatous polyp formation. Since no relationship between cullins expression and development of cancer on adenoma was found, the results of the present study may be useful explaining the initiation but not the progression of carcinogenesis in colorectal cancer. Further molecular and clinical studies are needed in order to delineate the clinical importance of these proteins in the management of colorectal cancer patients.