Reduced expression of Apaf-1 in colorectal adenocarcinoma correlates with tumor progression and aggressive phenotype.
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.
Paik
Seung Sam
SS
Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
Jang
Ki-Seok
KS
Song
Young Soo
YS
Jang
Si-Hyong
SH
Min
Kyueng-Whan
KW
Han
Hong Xiu
HX
Na
Woong
W
Lee
Kang Hong
KH
Choi
Dongho
D
Jang
Se Jin
SJ
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D014408:Biomarkers, Tumor