EZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma

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.

MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3′-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein

“…We focused on the effects of miRNAs on YTHDF2. Bioinformatics analysis predicted the potential miRNAs targeting the 3Ј-UTR of YTHDF2 by using three websites, including DIANA-microT, Targetscan, and MiRanda (33). Interestingly, eight candidate miRNAs could be predicted (Fig.…”

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

“…These data are in line with two recent reports that also described a tumour-suppressive function of miR-622 in HCC. Liu et al identified miR-622 as negative regulator of CXC chemokine receptor 4 (CXCR4) in HCC and showed that the inhibitory effect of miR-622 on migration of HCC cells strongly depends on CXCR4 suppression 32. In contrast, growth-suppressive effects of miR-622 on HCC cells were only slightly affected by its effect on CXCR4 expression 32.…”

“…Liu et al identified miR-622 as negative regulator of CXC chemokine receptor 4 (CXCR4) in HCC and showed that the inhibitory effect of miR-622 on migration of HCC cells strongly depends on CXCR4 suppression 32. In contrast, growth-suppressive effects of miR-622 on HCC cells were only slightly affected by its effect on CXCR4 expression 32. Song et al found that miR-622 negatively regulates mitogen-activated protein 4 kinase 4 (MAP4K4) in HCC, but overexpression of MAP4K4 only partially reversed the growth-suppressive effects of miR-622 on HCC cells 31.…”

Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis

“…For example, abnormal methylation of the HOXB4 gene leads to the inactivation of miR-10a, resulting in the activation of the NFjB signaling pathway in human HCC tumor tissues [96]. In addition, methylation-mediated repression of several microRNAs correlates with tumor aggressiveness of human HCC [97][98][99].…”