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Reduced Expression of Apaf-1 in Colorectal Adenocarcinoma Correlates with Tumor Progression and Aggressive Phenotype
Authors:Seung Sam Paik  Ki-Seok Jang  Young Soo Song  Si-Hyong Jang  Kyueng-Whan Min  Hong Xiu Han  Woong Na  Kang Hong Lee  Dongho Choi  Se Jin Jang
Affiliation:(1) Departments of Pathology, College of Medicine, Hanyang University, Seoul, Korea;(2) Departments of Surgery, College of Medicine, Hanyang University, Seoul, Korea;(3) Department of Surgery, College of Medicine, Soon Chun Hyang University, Seoul, Korea;(4) Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
Abstract:Background Apoptotic protease activating factor-1 (Apaf-1) is one of the key regulators in the mitochondrial apoptotic pathway, and the loss of Apaf-1 leads to cellular resistance against the apoptotic signals. We investigated the expression of Apaf-1 in colorectal tissues corresponding to the multistep carcinogenesis model to determine correlations between the clinicopathologic characteristics and the expression of this molecule and to evaluate the role of Apaf-1 in the development and progression of colorectal adenocarcinoma. Methods Immunohistochemistry for Apaf-1 was performed on the tissue microarray of 38 normal mucosal tissues, 46 adenomatous polyps, 529 colorectal adenocarcinomas, and 76 metastatic tumors. Results Normal colonic mucosa tissues and adenomas were positive for Apaf-1 with no exceptions (100%). However, in colorectal adenocarcinomas, 119 of 529 cases (22.5%) were positive and 410 cases (77.5%) were negative. Moreover, 67 of 76 metastatic cases (88.2 %) were negative and only nine cases (11.8%) were positive for Apaf-1 expression. In the analyses between Apaf-1 expression and clinicopathologic parameters, reduced expression of Apaf-1 correlated with left colon location (p < 0.001), deeper tumor invasion (p < 0.001), frequent lymph node metastasis ( p= 0.021), higher American Joint Committee on Cancer (AJCC) and Dukes’ stage (p = 0.02 and p = 0.001, respectively) and poorer differentiation (p < 0.001). The patient survival was significantly associated with age, histological grade, AJCC stage, and lymphovascular invasion, but not Apaf-1 expression (p = 0.478). Conclusions The results suggest that the loss of Apaf-1 expression is a relatively frequent late event and the loss of Apaf-1 expression may play an important role in tumorigenesis and tumor progression in colorectal adenocarcinoma. Seung Sam Paik and Ki-Seok Jang are equal contributors to this work. This work was presented at the 96th Annual Meeting of United States and Canadian Academy of Pathology, San Diego, California, March 24-30, 2007.
Keywords:Colorectal cancer  Apoptosis  Apoptotic protease activating factor 1  Tumor progression
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