Department of Hepatobiliary and Pancreatic Surgery, Fudan University Cancer Hospital, Fudan University, Shanghai, PR China.
Clin Cancer Res. 2010 May 15;16(10):2740-50. doi: 10.1158/1078-0432.CCR-09-2610. Epub 2010 May 11.
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.
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.
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.
beta-Catenin in HCC is activated by hypoxia and contributes to hypoxia-induced metastatic potential.
β-连环蛋白的异常激活导致肝癌（HCC）的恶性表型。缺氧也已知可促进 HCC 的侵袭和转移。然而，β-连环蛋白与缺氧的促侵袭作用之间的关联尚不清楚。我们研究了β-连环蛋白在 HCC 缺氧的促侵袭后果中的作用。
我们建立了体外和体内缺氧模型，以研究缺氧 HCC 细胞中β-连环蛋白的表达及其在缺氧诱导的侵袭性中的作用。使用 HCC 组织微阵列评估β-连环蛋白和/或缺氧诱导因子-1α（HIF-1α）的临床意义。
缺氧通过下调内源性降解机制诱导四种 HCC 细胞系中β-连环蛋白的过表达和/或细胞内积累，并促进 MHCC97 和 Hep3B 细胞的体外侵袭和体内转移。除了形态变化外，缺氧 MHCC97 和 Hep3B 细胞还表现出与上皮间质转化一致的分子改变，其特征为上皮细胞标志物（E-钙粘蛋白和斑联蛋白）的丢失和间充质标志物（波形蛋白和 N-钙粘蛋白）的上调，以及基质金属蛋白酶 2 的增加。然而，在这些缺氧细胞中沉默β-连环蛋白逆转了上皮间质转化并抑制了转移潜力。HCC 组织微阵列中β-连环蛋白的阳性表达与 HIF-1α的表达相关（P=0.034），HCC 中β-连环蛋白和 HIF-1α的共表达与总生存期和复发时间较短相关。
HCC 中的β-连环蛋白被缺氧激活，并有助于缺氧诱导的转移潜力。
