Loss of SIRT1 Histone Deacetylase Expression Correlates with Tumor Progression and Microsatellite Instability Phenotype in Colorectal Adenocarcinoma.
Young Jin Jun, Se Min Jang, Hulin Han, Hyun Jeong Kim, Seung Sam Paik, Ki-Seok Jang. College of Medicine, Hanyang University, Seoul, Republic of Korea
Background: The class III histone deacetylase SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mediate heterochromatin formation. SIRT1 has been reported to serve diverse roles in various biological processes, such as caloric restriction, apoptosis, neuronal protection, cell growth, differentiation, and tumorigenesis. In the view of tumorigenesis, there have been conflicting data supporting whether SIRT1 act as a tumor promoter or as a tumor suppressor.
Design: To elucidate whether SIRT1 is involved in the development and progression of colorectal cancer, we investigated SIRT1 protein expression, determined by immunohistochemistry, in human normal colonic mucosa (n=24), adenoma (n=52), adenocarcinoma (n=497) and metastatic tissue sample (n=126).
Results: All 24 normal colonic mucosa (100%) were positive for SIRT1 with no exception, and 42 (80.8%) of 52 adenomatous polyps were positive for SIRT1 and 10 (19.2%) were negative. However, 208 (41.9%) of 497 colorectal adenocarcinomas were positive for SIRT1 and 289 (58.1%) were negative. Moreover, 45 cases (35.7 %) of 126 metastatic tissue were positive for SIRT1 and 81 cases (64.3%) were negative. Collectively, the SIRT1 expression was gradually decreased during carcinogenesis and tumor progression. The correlations between SIRT1 expression and clinicopathologic parameters revealed that the loss of SIRT1 expression correlated with proximal tumor location, mucinous histology, and defective mismatch repair protein (MLH1 and MSH2) expression. This result suggests that the loss of SIRT1 expression is associated with microsatellite instability phenotype of colorectal adenocarcinoma. In survival analyses, the loss of SIRT1 expression was significantly correlated with overall survival (p = 0.027, log-rank test) in univariate analysis, but multivariate analysis failed to achieve the significance.
Conclusions: The SIRT1 expression was gradually decreased during normal-adenoma-adenocarcinoma-metastasis sequence, suggesting the possible role of SIRT1 on tumor suppression in colorectum.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 55, Wednesday Morning