Dataset Information

MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma.

ABSTRACT: NEK2 is a member of the NIMA-related family of serine/threonine centrosomal kinases. We analyzed the relationship between differential expression of NEK2 and hepatocellular carcinoma (HCC) patient outcomes after liver transplants. We also studied the microRNAs that affect NEK2 expression. Analysis of multiple microarrays in the Oncomine database revealed that NEK2 expression was higher in HCC tissues than adjacent normal liver tissues. High NEK2 expression correlated with tumor size, pathological grade and macro- and microvascular invasion. Consequently, patients exhibiting high NEK2 expression had poorer prognosis. This was corroborated by our multivariate analysis that showed NEK2 to be an independent prognostic factor for HCC patient survival. Further, high NEK2 expression promoted proliferation, colony formation, migration and invasion of HCC cell lines. Tumor xenograft data from Balb/c nude mice demonstrated that HCC cells with high NEK2 expression formed larger tumors than those with low NEK2 expression. Finally, we showed that miR-486-5p suppressed NEK2 by directly binding to its transcript 3'UTR. We also demonstrated an inverse relationship between miR-486-5p and NEK2 expression in HCC patients. These findings suggest miR-486-5p negatively regulates NEK2, which is a critical prognostic indicator of HCC patient survival after liver transplantation.

SUBMITTER: Fu SJ

PROVIDER: S-EPMC5581084 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma.

Fu Shun-Jun SJ Chen Jian J Ji Fei F Ju Wei-Qiang WQ Zhao Qiang Q Chen Mao-Gen MG Guo Zhi-Yong ZY Wu Lin-Wei LW Ma Yi Y Wang Dong-Ping DP Zhu Xiao-Feng XF He Xiao-Shun XS

Oncotarget 20170505 32

NEK2 is a member of the NIMA-related family of serine/threonine centrosomal kinases. We analyzed the relationship between differential expression of NEK2 and hepatocellular carcinoma (HCC) patient outcomes after liver transplants. We also studied the microRNAs that affect NEK2 expression. Analysis of multiple microarrays in the Oncomine database revealed that NEK2 expression was higher in HCC tissues than adjacent normal liver tissues. High NEK2 expression correlated with tumor size, pathologica ...[more]

PMID: 28881785

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Project description:HCC (hepatocellular carcinoma) is a major health threat for the Chinese population and has poor prognosis because of strong resistance to chemotherapy in patients. For instance, a considerable challenge for the treatment of HCC is sorafenib resistance. The aberrant glucose metabolism in cancer cells aerobic glycolysis is associated with resistance to chemotherapeutic agents. Drug-resistance cells and tumors were exposed to sorafenib to establish sorafenib-resistance cell lines and tumors. Western blotting and real-time PCR or IHC staining were used to analyze the level of CLCF1 in the sorafenib resistance cell lines or tumors. The aerobic glycolysis was analyzed by ECAR assay. The mechanism mediating the high expression of CLCF1 in sorafenib-resistant cells and its relationships with miR-130-5p was determined by bioinformatic analysis, dual luciferase reporter assays, real-time PCR, and western blotting. The in vivo effect was evaluated by xenografted with nude mice. The relation of CLCF1 and miR-30a-5p was determined in patients' samples. In this study, we report the relationship between sorafenib resistance and increased glycolysis in HCC cells. We also show the vital role of CLCF1 in promoting glycolysis by activating PI3K/AKT signaling and its downstream genes, thus participating in glycolysis in sorafenib-resistant HCC cells. Furthermore, we also show that miR-30a-5p directly targets CLCF1 and that sorafenib-mediated suppression of miR-30a-5p results in the upregulation of CLCF1 in HCC cells resistant to sorafenib. We also found that when a cholesterol modified agomiR-30a-5p was delivered systemically to mice harboring sorafenib-resistant HCC tumors, tumor growth decreased significantly. There is an uncharacterized mechanism of biochemical resistance to hormone therapies orchestrated by the miR-30a-5p/CLCF1 axis to mediate sorafenib resistance and aerobic glycolysis in HCC. Therefore, this study indicates that targeting the miR-30a-5p/CLCF1 axis may hold promise for therapeutic intervention in HCC sorafenib resistance patients.

Dataset Information

MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma.

Publications

MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma.

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