Double‐negative feedback loop between MicroRNA‐422a and forkhead box (FOX)G1/Q1/E1 regulates hepatocellular carcinoma tumor growth and metastasis. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Zhang, Jin; Yang, Yun; Yang, Tian; Yuan, Shengxian; Wang, Ruoyu; Pan, Zeya; Yang, Yuan; Huang, Gang; Gu, Fangming; Jiang, Beige; Lin, Chuan; Zhou, Weiping
• Is Part Of: Hepatology. Volume 61:Issue 2(2015:Feb.)
• Page Start: 561
• Page End: 573
• Publication Date: 2015-02
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27491
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic>. 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 <italic>in vitro</italic> and <italic>in vivo</italic>. 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. <italic>Conclusion</italic>: Our findings show the critical roles of miR‐422a and its targets—FOXG1, FOXQ1, and FOXE1—in the regulation of HCC development and provide new potential candidates for HCC therapy. (H<sc>epatology</sc> 2015;61:561‐573)</p> </abstract>