Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis.
OBJECTIVE
Aberrant activation of beta-catenin contributes to the malignant phenotype in hepatocellular carcinoma (HCC). Hypoxia is also known to promote HCC invasion and metastasis. However, the association between beta-catenin and the proinvasive role of hypoxia remains unclear. We investigated the role of beta-catenin in the proinvasive consequences of hypoxia in HCC.


METHODS
We established in vitro and in vivo hypoxic models to investigate the expression of beta-catenin in hypoxic HCC cells and its role in hypoxia-induced aggressiveness. The clinical significance of beta-catenin and/or hypoxia-induced factor-1alpha (HIF-1alpha) was evaluated using HCC tissue microarrays.


RESULTS
Hypoxia induced beta-catenin overexpression and/or intracellular accumulation in four HCC cell lines through downregulating the endogenous degradation machinery, and promoted in vitro invasion and in vivo metastasis of MHCC97 and Hep3B cells. Besides morphologic changes, hypoxic MHCC97 and Hep3B cells exhibited molecular alterations consistent with epithelial-mesenchymal transition, characterized by the loss of epithelial cell markers (E-cadherin and plakoglobin) and upregulation of mesenchymal markers (vimentin and N-cadherin), as well as the increase of matrix metalloproteinase 2. However, silencing beta-catenin in these hypoxic cells reversed epithelial-mesenchymal transition and repressed metastatic potential. Positive expression of beta-catenin in HCC tissue microarray was associated with the expression of HIF-1alpha (P=0.034), and coexpression of beta-catenin and HIF-1alpha in HCC was correlated with shorter overall survival and time to recurrence.


CONCLUSIONS
beta-Catenin in HCC is activated by hypoxia and contributes to hypoxia-induced metastatic potential.
Liu
Liang
L
Department of Hepatobiliary and Pancreatic Surgery, Fudan University Cancer Hospital, Fudan University, Shanghai, PR China.
Zhu
Xiao-Dong
XD
Wang
Wen-Quan
WQ
Shen
Yuan
Y
Qin
Yi
Y
Ren
Zheng-Gang
ZG
Sun
Hui-Chuan
HC
Tang
Zhao-You
ZY
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051176:beta Catenin