期刊
HEPATOLOGY
卷 61, 期 2, 页码 561-573出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.27491
关键词
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资金
- Science Fund for Creative Research Groups, NSFC, China [81221061]
- National High Technology Research and Development Program of China (863 program) [2013AA032202]
- State Key Infection Disease Project of China [2012ZX10002010]
- Shanghai Rising-Star Program [12QA1404900]
- Innovation Program of Shanghai Municipal Education Commission [11ZZ76]
- Shanghai Program for Excellent Talents in Health Systems [XYQ2011034]
- National Natural Science Foundation for Youths of China [81101578]
Growing evidence indicates that the aberrant expression of microRNAs (miRNAs) contributes to tumor development; however, the function of miRNAs in human hepatocellular carcinoma (HCC) remains largely undefined. In this study, we report that microRNA-422a (miR-422a) is significantly down-regulated in HCC tumor samples and cell lines compared with normal controls, and its expression level is negatively correlated with pathological grading, recurrence, and metastasis. The restoration of miR-422a expression in HCC tumor cells significantly inhibited cell proliferation and migration in vitro. At the same time, the overexpression of miR-422a in HCC tumor cells significantly inhibits tumor growth and liver metastasis in xenograft tumor models. A mechanistic study identified three genes, forkhead box G1 (FOXG1), FOXQ1, and FOXE1, as miR-422a targets in the regulation of HCC development. We also investigated the function of the three targets themselves in HCC tumorigenesis using RNAi manipulation and demonstrated that the knockdown of these targets led to significant inhibition of tumor cell proliferation and migration both in vitro and in vivo. More interestingly, a potential miR-422a promoter region was identified. Both the promoter activity and miR-422a expression were negatively regulated by the three targets, indicating that a double-negative feedback loop exists between miR-422a and its targets. Moreover, we explored the therapeutic potential of miR-422a in HCC treatment and found that the therapeutic delivery of miR-422a significantly inhibited tumor development in a xenograft tumor model and a diethylnitrosamine-induced primary HCC model. Conclusion: Our findings show the critical roles of miR-422a and its targetsFOXG1, FOXQ1, and FOXE1in the regulation of HCC development and provide new potential candidates for HCC therapy. (Hepatology 2015;61:561-573)
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