Down-regulation of tumor suppressor gene PTEN, overexpression of p53, plus high proliferating cell nuclear antigen index predict poor patient outcome of hepatocellular carcinoma after resection.
We aimed to evaluate the interaction of two tumor suppressor genes PTEN and p53 and their relationship with cell cycle protein proliferating cell nuclear antigen (PCNA) in hepatocellular carcinoma (HCC). A total of 124 resected HCC paraffin specimens were collected from 1987 to 1999 for immunohistochemistry. Expression of PTEN, p53 and PCNA in HCC were analyzed for clinicopathologic correlation. The study revealed decreased or absent PTEN immunostaining (PTEN down-regulation) in 42.7% and positive p53 (p53+) immunostaining in 41.9% of HCC. There was a positive correlation between PTEN down-regulation and p53 (+) (P=0.001). PTEN down-regulation or p53 (+) correlated with increased HCC dedifferentiation, advanced pathologic stages and high PCNA labeling index (LI) of tumors (P<0.05). Patients with either PTEN down-regulation, p53 (+), or high PCNA LI had shorter survival and higher recurrence rates than patients with intact PTEN expression, p53 (-), or low PCNA LI respectively (P<0.05). By combining the three genes, patients with all PTEN down-regulation (+)/p53 (+)/high PCNA LI had the shortest overall survival (P<0.001) and the highest recurrence rates (P<0.001), followed by patients with two, one and none of three events accordingly. Combination of PTEN/p53/PCNA represented an independent prognostic factor for tumor recurrence and disease-specific survival (P<0.05). In conclusion, the down-regulated PTEN expression and p53 over-expression are involved in the pathogenesis of HCC. They correlate with high PCNA expression, HCC de-differentiation and advanced HCC stages. A combination of the three genes predicts patient outcome more powerfully than any of the individual genes.
Hu
Tsung-Hui
TH
Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 813, Taiwan.
Wang
Chih-Chi
CC
Huang
Chao-Cheng
CC
Chen
Chao-Long
CL
Hung
Chao-Hung
CH
Chen
Chien-Hung
CH
Wang
Jing-Houng
JH
Lu
Sheng-Nan
SN
Lee
Chuan-Mo
CM
Changchien
Chi-Sin
CS
Tai
Ming-Hong
MH
D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis; D017741:Survivors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human