Down-regulation of FHIT inhibits apoptosis of colorectal cancer: mechanism and clinical implication.
Fragile histidine triad (FHIT) gene, a candidate tumor suppressor gene located at 3p14.2, has been shown to be involved in carcinogenesis of many human tissues, including digestive tract tissues. However, the expression and role of FHIT in the initiation and the development of the colorectal cancer (CRC) are poorly understood. In our present study, we have demonstrated that the FHIT gene exhibits significantly decreased expression in human CRC compared to colorectal adenoma and normal colorectal tissue by tissue microarray (TMA). The positive of FHIT gene expression in normal colorectal tissue, adenoma and adenocarcinoma were 93.75%, 68.75% and 46.25%, respectively. We showed that decreased FHIT expression was significantly correlated with the progression of colorectal carcinoma (P<0.05) as well as differentiation and lymph node metastasis (P<0.05). Two somatic mutations in the FHIT gene were also detected in human CRC. The presence of these mutations correlated significantly with decreased FHIT expression in the human CRC. In addition, we identified decreased FHIT expression resulting in apoptosis inhibition and decreasing apoptosis associated with abnormal levels of some pro- and anti-apoptotic proteins (Bax, Bcl-2 and Survivin) by TUNEL and TMA. Our results demonstrated that the mutation in the FHIT gene significantly reduced FHIT expression in human CRC. Both TUNEL and TMA experiments demonstrated significantly inhibited apoptosis by down-regulation of Bax and up-regulation of Survivin and Bcl-2. Collectively, these studies identify the mechanism by which an important tumor suppressor gene, FHIT, inactivated specifically in human CRC, and contributes to our understanding of the mechanism of colorectal carcinogenesis.
Cao
Jie
J
Department of Gastrointestinal Surgery, Affiliated Guangzhou First People's Hospital, Guangzhou Medical College, 1# Pang Fu Road, Guangzhou 510180, China. czhongt@126.com
Li
Wanglin
W
Xie
Jie
J
Du
Hong
H
Tang
Weibiao
W
Wang
Hui
H
Chen
Xiwen
X
Xiao
Wanqing
W
Li
Yuyuan
Y
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D019254:Genes, bcl-2; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D016019:Survival Analysis; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D000099170:Bis(5'-adenosyl)triphosphatase; C107489:BIRC5 protein, human