EZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma
Haiou Liu1, Yidong Liu2, Weisi Liu2
1Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China.
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.
Insights
Aberrant CXC chemokine receptor 4 (CXCR4) overexpression drives hepatocellular carcinoma (HCC) progression. Targeting the EZH2/miR-622/CXCR4 pathway offers a potential therapeutic strategy for HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- CXC chemokine receptor 4 (CXCR4) plays a role in hepatocellular carcinoma (HCC) progression.
- The specific molecular mechanisms and therapeutic potential of CXCR4 in HCC are not fully understood.
Purpose of the Study:
- To elucidate the role of CXCR4 in HCC development and identify its regulatory mechanisms.
- To evaluate CXCR4 as a potential therapeutic target and prognostic marker for HCC.
Main Methods:
- CXCR4 knockdown, AMD3100, and neutralizing antibodies were used to suppress CXCR4 activity.
- MicroRNA (miRNA) library screening identified miR-622 as a regulator of CXCR4.
- Quantitative PCR, Western blotting, and methylation-specific PCR were employed to analyze gene and protein expression, and epigenetic modifications.
Main Results:
- Aberrant CXCR4 overexpression correlated with poor prognosis and aggressive HCC characteristics.
- Suppression of CXCR4 inhibited hepatoma cell tumorigenesis in vitro and in vivo.
- miR-622 directly targets CXCR4 and is transcriptionally repressed by EZH2 via H3K27 trimethylation and promoter methylation.
- EZH2-mediated loss of miR-622 was associated with CXCR4 overexpression and unfavorable HCC prognosis.
Conclusions:
- The EZH2/miR-622/CXCR4 axis promotes HCC tumorigenesis.
- This pathway represents a potential adverse prognostic factor and therapeutic target for HCC.
