Abstract
BackgroundHigh invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT).MethodsThe expression of EMT markers was analyzed by immunohistochemistry. Effect of hypoxia on induction of EMT and ability of cell migration and invasion were performed. Luciferase reporter system was used for evaluation of Snail regulation by hypoxia-inducible factor -1α (HIF-1α).ResultsWe found that overexpression of HIF-1α was observed in HCC liver tissues and was related to poor prognosis of HCC patients. HIF-1α expression profile was correlated with the expression levels of SNAI1, E-cadherin, N-cadherin and Vimentin. Hypoxia was able to induce EMT and enhance ability of invasion and migration in HCC cells. The same phenomena were also observed in CoCl2-treated cells. The shRNA-mediated HIF-1α suppression abrogated CoCl2-induced EMT and reduced ability of migration and invasion in HCC cells. Luciferase assay showed that HIF-1α transcriptional regulated the expression of SNAI1 based on two hypoxia response elements (HREs) in SNAI1 promoter.ConclusionsWe demonstrated that hypoxia-stabilized HIF1α promoted EMT through increasing SNAI1 transcription in HCC cells. This data provided a potential therapeutic target for HCC treatment.
Highlights
High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC)
Expression of hypoxia and epithelial-mesenchymal transition (EMT) related genes in human HCC In order to know whether hypoxia status is related to EMT in HCC, we firstly investigated expression levels of hypoxia-inducible factor -1α (HIF-1α), HIF-2α, SNAI1, Twist, E-cadherin, N-cadherin and Vimentin in a tissue array containing 66 HCC samples from human patients by immunohistochemistry
HIF-1α and SNAI1 expression was detected in 65% (43/66) and 59% (39/66) of tumor samples, respectively
Summary
High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). We investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT). Metastasis is the main cause of deaths for patients with many solid cancers. 90% of deaths caused by cancers result from the metastatic spread of primary tumors [1]. Hypoxia is a critical microenvironment in tumor pathogenesis. It occurs in series of distinct steps that include tumor cell invasion, intravasation, extravasation and proliferation. There is a close relationship between hypoxia and tumor metastasis and poor prognosis. Several mechanisms have been proposed to explain how hypoxia might lead to a poor prognosis in the clinical settings, and none of which are mutually exclusive [4,24,25,26,27]
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