Activation of β-Catenin by Hypoxia in Hepatocellular Carcinoma Contributes to Enhanced Metastatic Potential and Poor Prognosis

Abstract

Purpose: Aberrant activation of β-catenin contributes to the malignant phenotype in hepatocellular carcinoma (HCC). Hypoxia is also known to promote HCC invasion and metastasis. However, the association between β-catenin and the proinvasive role of hypoxia remains unclear. We investigated the role of β-catenin in the proinvasive consequences of hypoxia in HCC.Experimental Design: We established in vitro and in vivo hypoxic models to investigate the expression of β-catenin in hypoxic HCC cells and its role in hypoxia-induced aggressiveness. The clinical significance of β-catenin and/or hypoxia-induced factor-1α (HIF-1α) was evaluated using HCC tissue microarrays.Results: Hypoxia induced β-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 β-catenin in these hypoxic cells reversed epithelial-mesenchymal transition and repressed metastatic potential. Positive expression of β-catenin in HCC tissue microarray was associated with the expression of HIF-1α (P = 0.034), and coexpression of β-catenin and HIF-1α in HCC was correlated with shorter overall survival and time to recurrence.Conclusion: β-Catenin in HCC is activated by hypoxia and contributes to hypoxia-induced metastatic potential. Clin Cancer Res; 16(10); 2740-50. ©2010 AACR.The expansion of tumors and the inadequacy of their local vasculature results in hypoxia (1). This is a common feature of hepatocellular carcinoma (HCC) and is associated with poor tumor outcome (2). Recent studies have shown that hypoxia promotes tumor invasion and metastasis through the activation of several signaling pathways, such as Ras-extracellular signal-regulated kinase, which modulate hypoxia-related biological effects (3). These include increased glycolysis, induction of angiogenesis, regulation of pH, and, notably, arrest of cell proliferation (4).The Wnt/β-catenin pathway is an important signaling pathway in HCC (5). Although it is involved in multiple biological effects in HCC, proproliferation is regarded as one of the most promalignant mechanisms (5, 6). β-Catenin is the chief downstream effector of this pathway. It has been reported that one third of HCCs are associated with the aberrant expression of β-catenin (5, 7).In this study, we examined alterations in β-catenin expression in hypoxic HCC cells and evaluated its significance in hypoxia-induced metastatic phenotypes. These experiments were based on several recent clinical and preclinical observations. First, given the critical role of β-catenin in the stimulation of HCC cell prolifer...

Prognostic significance of c-Met, β-catenin and FAK in patients with hepatocellular carcinoma following surgery

“…Numerous studies have reported that β-catenin overexpression in the cytoplasm and/or nucleus is correlated with cancer metastasis and poor prognosis (43)(44)(45)(46)(47)(48)(49)(50)(51). In the present study, higher Edmondson grade, poor TNM stage and positive portal vein invasion cases were identified to have increased cytoplasmic expression of β-catenin.…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…This expression pattern was accompanied by changes in E-cadherin expression, suggesting that b-catenin plays an important role in the metastasis of colorectal cancer, participating in EMT at the invasive front and in MET in metastases (13,55). In support of these findings, it was observed that silencing b-catenin in hypoxic MHCC97 and Hep3B cells also reversed EMT (56). Using a variant of the human cell line LIM1863 (LIM1863-Mph), Vincan and colleagues (57,58) established a unique model of colorectal cancer morphogenesis and showed that FZD7 plays a pivotal role in phenotype transitions, suggesting that Wnt signaling participates in orchestrating colorectal cancer morphogenesis.…”

Hypoxic microenvironment promotes proliferation and invasion of non-small cell lung cancer A549 Cells through Wnt/β-catenin signaling pathway

“…All these studies have shown that β-catenin is highly expressed in the above tumor tissues. In liver cancer cells, Wnt/β-catenin signaling pathway can promote the invasion and metastasis of cells through enhancing the hypoxia-induced epithelial-mesenchymal transition, and the expression of β-catenin is negatively correlated with the survival duration of patients after resection [25,26]. Also, in colorectal cancer cells, hypoxic environment can facilitate cell growth and invasion through activation of Nur77-β-catenin loop [27].…”