Abstract
The CXC chemokine receptor 4 (CXCR4) exerts a variety of functions at different steps of hepatocellular carcinoma (HCC) progression. The molecular mechanisms and therapeutic value of CXCR4 in the development of HCC remain undefined. Here we show that aberrant CXCR4 overexpression is associated with poor prognosis and aggressive characteristics of HCC. Suppression of CXCR4 activity via CXCR4 knockdown, AMD3100 or neutralizing antibody administration inhibits hepatoma cell tumorigenesis in vitro and in vivo. CXCR4 overexpression displays the opposite effects. Using Mir library screening we identify miR-622 as a regulator of CXCR4. Further studies show that miR-622 directly target the 3′ untranslated region of CXCR4 and is transcriptionally repressed by EZH2-induced H3K27 trimethylation and promoter methylation. EZH2/miR-622 promotes tumorigenesis through CXCR4. EZH2-mediated loss of miR-622 is found to correlate with CXCR4 overexpression and unfavourable prognosis in HCC patients. This study establishes EZH2/miR-622/CXCR4 as a potential adverse prognostic factor and therapeutic target for HCC patients.
Highlights
The CXC chemokine receptor 4 (CXCR4) exerts a variety of functions at different steps of hepatocellular carcinoma (HCC) progression
We identify CXCR4 overexpression in a subset of HCCs, which contributing to hepatoma cell proliferation, colony formation, migration and survival
A comprehensive miRNA analysis reveals that CXCR4 expression regulated by miR-622, which is epigenetically downregulated by enhancer of zeste homologue 2 (EZH2)
Summary
The CXC chemokine receptor 4 (CXCR4) exerts a variety of functions at different steps of hepatocellular carcinoma (HCC) progression. This study establishes EZH2/miR-622/CXCR4 as a potential adverse prognostic factor and therapeutic target for HCC patients. The CXCR4/CXCL12 has multiple functions at various points in the progression of hepatocellular carcinomas (HCCs). Both autocrine and/or paracrine effects of this pathway have been shown to maintain cancer growth, induce angiogenesis and aid escape of immune surveillance[5]. In the context of HCC, aberrant expression of specific miRNAs are closely associated with tumour cell proliferation, migration and invasion by targeting proteins involved in these cellular functions[14,15,16]. EZH2/miR-622 pathway is significantly associated with CXCR4 expression and poor prognosis of HCC patients. The alteration in the EZH2/miR-622/CXCR4 pathway contributes to tumour development and represents therapeutic targets
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