Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The role of autophagy and the prognostic value of autophagic genes are largely unknown in HCC. Here, we showed decreased expression of autophagic genes and their corresponding autophagic activity and increased expression of the antiapoptotic gene Bcl-xL in HCC cell lines compared with a normal hepatic cell line. We also found decreased expression of the autophagic gene Beclin 1 in 44 HCC tissue samples compared with adjacent nontumor tissues. In addition, we found that the most aggressive malignant HCC cell lines and HCC tissues with recurrent disease displayed much lower autophagic levels, especially when Bcl-xL was overexpressed. Interestingly, in a tissue microarray study consisting of 300 HCC patients who underwent curative resection, the expression of Beclin 1 was only significantly correlated with disease-free survival (DFS; P < 0.0001) and overall survival (OS; P < 0.0001) in the Bcl-xL(+) group. Multivariate and univariate analyses also revealed that Beclin 1 expression was an independent predictor for DFS and OS in Bcl-xL(+) patients. In addition, we found a significant correlation between Beclin 1 expression and tumor differentiation in Bcl-xL(+) but not in Bcl-xL(-) HCC patients. In conclusion, our data showed expression of autophagic genes and their corresponding autophagic activities were suppressed in HCC. The autophagy defects synergized with altered apoptotic activity might facilitate tumor malignant differentiation, which results in a more aggressive cancer cell phenotype and poor prognosis of HCC.
Ding
Zhen-Bin
ZB
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Shanghai 200032, China.
Shi
Ying-Hong
YH
Zhou
Jian
J
Qiu
Shuang-Jian
SJ
Xu
Yang
Y
Dai
Zhi
Z
Shi
Guo-Ming
GM
Wang
Xiao-Ying
XY
Ke
Ai-Wu
AW
Wu
Bin
B
Fan
Jia
J
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D001343:Autophagy; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000401:mortality* / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality* / Q000473:pathology*; D008565:Membrane Proteins / Q000032:analysis; D010641:Phenotype; D011379:Prognosis; D046888:Tissue Array Analysis; D051020:bcl-X Protein / Q000032:analysis
D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D051020:bcl-X Protein