HIF-1α plays a role in the chemotactic migration of hepatocarcinoma cells through the modulation of CXCL6 expression

Abstract

Background/Aims: Hypoxia promotes the progression and metastasis of hepatocellular carcinoma (HCC). Hypoxia inducible factor-α (HIF-lα) regulates the expression of various chemokines involved in tumor growth, angiogenesis and metastasis. Methods: The role of HIF-la in HCC tumor growth and invasion and the prognosis of patients with HCC was investigated in cell lines and patient samples. HIF-lα mRNA and protein levels were assessed by gRT-PCR and western blotting. Silencing of HIF-lα downregulated the expression of granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR+ chemokine, in HCC cells, and a luciferase assay showed that HIF-lα binds to a hypoxia response element in the promoter of CXCL6 and regulates its transcription. Induction of HIF-lα by hypoxia promoted the migration and invasion of HCC cells in vitro, and this effect was suppressed by an anti-CXCL6 antibody. Results: HIF-la is upregulated in HCC cell lines and tissues and its effect on promoting invasion and metastasis is mediated by its direct interaction with the pro-angiogenic chemokine CXCL6. CXCL6 expression was associated with poor prognosis of HCC patients. αConclusion: HIF-lα promotes HCC progression and metastasis by upregulating CXCL6 transcription in HCC cells, providing a potential novel therapeutic target for the treatment of HCC.