title: Loss of SIRT1 histone deacetylase expression associates with tumour progression in colorectal adenocarcinoma.
abstract: BACKGROUND
  The class III histone deacetylase SIRT1 is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, and has been reported to serve diverse roles in various biological processes, such as caloric restriction, apoptosis, neuronal protection, cell growth, differentiation and tumourigenesis. With respect to tumourigenesis, there have been conflicting data supporting whether SIRT1 act as a tumour promoter or as a tumour suppressor.
  
  
  METHODS
  SIRT1 protein expression, determined by immunohistochemistry, was investigated in human normal colonic mucosa, adenoma, adenocarcinoma and metastatic tissue samples.
  
  
  RESULTS
  All normal colonic mucosa showed SIRT1 expression with no exception, and 42 (80.8%) of 52 adenomatous polyps were positive for SIRT1. However, only 208 (41.9%) of 497 colorectal adenocarcinomas were positive. Moreover, 45 (35.7%) of 126 metastatic tissues were positive. Collectively, the SIRT1 expression was gradually decreased during carcinogenesis and tumour progression. The associations between SIRT1 expression and clinicopathological parameters revealed that loss of SIRT1 expression was associated with proximal tumour location, mucinous histology and defective mismatch repair protein expression. This suggests that loss of SIRT1 expression is associated with the microsatellite instability phenotype of colorectal adenocarcinoma. In survival analyses, the loss of SIRT1 expression was significantly associated with overall survival (p=0.027, log-rank test) in univariable analysis, but multivariable analysis failed to achieve significance.
  
  
  CONCLUSIONS
  SIRT1 expression was gradually decreased during the normal-adenoma-adenocarcinoma-metastasis sequence, suggesting a possible role of SIRT1 in tumour suppression in the colorectum, and a probable link to the microsatellite instability pathway.
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Si-Hyong
authors.initials: SH
authors.lastname: Jang
authors.forename: Kyeung-Whan
authors.initials: KW
authors.lastname: Min
authors.forename: Seung Sam
authors.initials: SS
authors.lastname: Paik
authors.forename: Ki-Seok
authors.initials: KS
authors.lastname: Jang
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D018256:Adenomatous Polyps / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016009:Chi-Square Distribution; D003111:Colonic Polyps / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D056910:Republic of Korea; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D056564:Sirtuin 1 / Q000032:analysis*; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D045643:DNA Repair Enzymes