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MicroRNA-761 is upregulated in hepatocellular carcinoma and regulates tumorigenesis by targeting Mitofusin-2.

ABSTRACT: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related deaths worldwide. The fate of a cell is determined by the balance between the processes of fission and fusion that constantly occur in the mitochondria of cells. We previously showed that overexpression of Mitofusin-2 can induce apoptosis in HCC cells by triggering an influx of Ca(2+) into the mitochondria from the ER. The function of Mitofusin-2 has been studied extensively, but the mechanism underlying the post-transcriptional regulation of Mitofusin-2 has not been elucidated. In the present study, we aimed to identify the mechanism of Mitofusin-2 regulation in HCC. We demonstrated that Mitofusin-2 is a direct target of miR-761, which was found to be upregulated in HCC tissues. Furthermore, a miR-761 inhibitor impaired mitochondrial function by upregulating Mitofusin-2 and effectively repressed tumor growth and metastasis both in vivo and in vitro. Our findings provide new insight into the mechanism underlying Mitofusin-2 regulation and the potential role of miR-761 in HCC, making it a potential candidate for use in HCC therapy in the future.

SUBMITTER: Zhou X

PROVIDER: S-EPMC4832850 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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MicroRNA-761 is upregulated in hepatocellular carcinoma and regulates tumorigenesis by targeting Mitofusin-2.

Zhou Xiaohu X Zhang Linshi L Zheng Bichun B Yan Yingcai Y Zhang Yuan Y Xie Haiyang H Zhou Lin L Zheng Shusen S Wang Weilin W

Cancer science 20160330 4

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related deaths worldwide. The fate of a cell is determined by the balance between the processes of fission and fusion that constantly occur in the mitochondria of cells. We previously showed that overexpression of Mitofusin-2 can induce apoptosis in HCC cells by triggering an influx of Ca(2+) into the mitochondria from the ER. The function of Mitofusin-2 has been studied extensively, but the m ...[more]

PMID: 26845057

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Project description:PurposeHepatocellular carcinoma (HCC) is a highly aggressive malignant tumor, the prognosis of which remains poor. Recently, microRNAs have been reported to play crucial functions in multiple tumors, including HCC. However, the molecular mechanisms of miR-370 in HCC still remain largely unknown. The present study focused on the effects of miR-370 on HCC migration, invasion, and epithelial-mesenchymal transition (EMT).Materials and methodsWe investigated the key roles and possible regulatory mechanism of miR-370 in regulating HCC metastasis with functional assays, such as transwell assay. Quantitative real-time PCR (qRT-PCR) was used to detect miR-370 and guanylylcyclase domain containing 1 (GUCD1) expression in HCC tissues and cells. Subsequently, we performed transwell assays to determine the functions of miR-370 in HCC cell invasion and migration. Western blot was used to determine protein expressions of relevant genes. Luciferase reporter assays were conducted to confirm the target gene of miR-370.ResultsqRT-PCR analysis demonstrated that miR-370 was dramatically downregulated in HCC. Moreover, downregulated miR-370 was found to be associated with poor survival and adverse clinicopathologic characteristics of HCC patients. Transwell assays revealed that miR-370 overexpression dramatically suppressed HCC invasion and migration. Meanwhile, miR-370 restoration prominently inhibited EMT progression in HCC cells. Luciferase reporter assays confirmed GUCD1 as a downstream target gene of miR-370. GUCD1 expression in HCC tissues was prominently increased and inversely correlated with miR-370 expression. Furthermore, GUCD1 was verified as mediating the suppressive influence of miR-370 on cell metastasis and EMT in HCC.ConclusionTaken together, our study confirmed that miR-370 suppressed HCC cell metastasis and EMT via regulating GUCD1. Accordingly, the miR-370/GUCD1 axis may potentially acts as attractive therapeutic targets and novel biomarkers for HCC treatment.

Project description:Metastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial-mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT can be regulated by microRNAs (miRNAs). The aim of this study was to investigate the role of miR-26b in modulating epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), as well as to identify its underlying mechanism of action.The expression level of miR-26b was assessed in multiple HCC cell lines (HepG2, MHCC97H, Hep3B, MHCC97L, HCCC9810, BEL-7402, Huh7 and QGY-7703), as well as in liver tissue from patients with HCC. Follow-up studies examined the effects of a miR-26b mimic (increased expression) and a miR-26b inhibitor (decreased expression) on markers of EMT, wound healing and cell migration. The molecular target of miR-26b was also identified using a computer algorithm and confirmed experimentally.MiR-26b expression was decreased in HCC cell lines and was inversely correlated with the grade of HCC. Increased expression of miR-26b inhibited the migration and invasiveness of HCC cell lines, which was accompanied by decreased expression of the epithelial marker E-cadherin and increased expression of the mesenchymal marker vimentin, at both the mRNA and protein expression levels. A binding site for miR-26b was theoretically identified in the 3'UTR of USP9X. Further studies revealed that overexpression of miR-26b repressed the endogenous level of USP9X protein expression. Overexpression of miR-26b also repressed Smad4 expression, whereas its inhibition elevated Smad4 expression.Taken together, our results indicate that miR-26b were inhibited in HCC. In HCC cell lines, miR-26b targeted the 3'UTR of USP9X, which in turn affects EMT through Smad4 and the TGF-? signaling pathway. Our analysis of clinical HCC samples verifies that miR-26b also targets USP9X expression to inhibit the EMT of hepatocytes. Thus, miR-26b may have some effects on the EMT of HCC cells.

Project description:Hepatocellular carcinoma (HCC) remains one of the most refractory malignancies worldwide. Schlafen family member 11 (SLFN11) has been reported to play an important role in inhibiting the production of human immunodeficiency virus 1 (HIV-1). However, whether SLFN11 also inhibits hepatitis B virus (HBV), and affects HBV-induced HCC remain to be systematically investigated. Methods: qRT-PCR, western blot and immunohistochemical (IHC) staining were conducted to investigate the potential role and prognostic value of SLFN11 in HCC. Then SLFN11 was stably overexpressed or knocked down in HCC cell lines. To further explore the potential biological function of SLFN11 in HCC, cell counting kit-8 (CCK-8) assays, colony formation assays, wound healing assays and transwell cell migration and invasion assays were performed in vitro. Meanwhile, HCC subcutaneous xenograft tumor models were established for in vivo assays. Subsequently, immunoprecipitation (IP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses were applied to understand the molecular mechanisms of SLFN11 in HCC. Co-IP, immunofluorescence and IHC staining were used to analyze the relationship between ribosomal protein S4 X-linked (RPS4X) and SLFN11. Finally, the therapeutic potential of SLFN11 with mTOR pathway inhibitor INK128 on inhibiting HCC growth and metastasis was evaluated in vitro and in vivo orthotopic xenograft mouse models. Results: We demonstrate that SLFN11 expression is decreased in HCC, which is associated with shorter overall survival and higher recurrence rates in patients. In addition, we show that low SLFN11 expression is associated with aggressive clinicopathologic characteristics. Moreover, overexpression of SLFN11 inhibits HCC cell proliferation, migration, and invasion, facilitates apoptosis in vitro, and impedes HCC growth and metastasis in vivo, all of which are attenuated by SLFN11 knockdown. Mechanistically, SLFN11 physically associates with RPS4X and blocks the mTOR signaling pathway. In orthotopic mouse models, overexpression of SLFN11 or inhibition of mTOR pathway inhibitor by INK128 reverses HCC progression and metastasis. Conclusions: SLFN11 may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the mTOR signaling pathway via RPS4X in HCC. Our study may therefore offer a novel therapeutic strategy for treating HCC patients with the mTOR pathway inhibitor INK128.

Dataset Information

MicroRNA-761 is upregulated in hepatocellular carcinoma and regulates tumorigenesis by targeting Mitofusin-2.

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MicroRNA-761 is upregulated in hepatocellular carcinoma and regulates tumorigenesis by targeting Mitofusin-2.

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