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      Mitofusin-2 acts as biomarker for predicting poor prognosis in hepatitis B virus related hepatocellular carcinoma

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          Abstract

          Objective

          To investigate the expression of Mitofusin-2 (MFN2) in HCC tissues and its role in the development of HCC.

          Methods

          A total of 107 HCC specimens were collected for tissue microarray analysis and immunohistochemistry (IHC) analysis. The relationship between MFN2 expression and clinical features of patients with HCC was analyzed.

          Results

          Expression level of MFN2 in HCC tissues was 0.92 ± 0.78, significantly lower than that of matched paracancerous liver tissues (1.25 ± 0.75). Patients with low expression of MFN2 had significantly higher rates of cirrhosis than those with high expression of MFN2 ( P = 0.049). Kaplan-Meier survival analysis showed that HCC patients with low expression of MFN2 had a worse prognosis in overall survival than HCC patients with high expression of MFN2 ( P = 0.027). Patients with high expression of MFN2 had a better prognosis in disease-free survival compared with HCC patients with low expression of MFN2 ( P = 0.047). Vascular invasion and MFN2 expression were shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis showed that vascular invasion ( P < 0.001) and MFN2 expression ( P = 0.045) were independent prognostic factors for overall survival. Vascular invasion ( P < 0.001) and MFN2 expression ( P = 0.042) were independent risk factors associated with disease-free survival.

          Conclusion

          Our data revealed that MFN2 expression was decreased in HCC samples. High MFN2 expression was correlated with longer survival times in patients with HCC and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for the prognostic prediction of HCC and a potential therapeutic target for the disease.

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          Most cited references19

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          Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

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            MFN2 suppresses cancer progression through inhibition of mTORC2/Akt signaling

            The mitochondrial GTPase mitofusin-2 (MFN2) has previously been reported to play a role in regulating cell proliferation, apoptosis and differentiation in a number of cell types. Here, we report that breast cancer patients with low MFN2 expression are associated with poor prognosis as compared to patients with high MFN2 expression. We find that MFN2 knockout from MCF7 and A549 cells via Crispr/Cas9 greatly promotes cell viability, colony formation, and invasion of cancer cells in vitro and in vivo, which were confirmed by colony formation assay, transwell invasion assay, and tumor xenograft model. Signaling analyses suggest the mammalian target of rapamycin complex 2 (mTORC2)/Akt signaling pathway is highly elevated in MFN2 knockout cancer cells. The elevated mTORC2 promotes cancer cell growth and metastasis via AktS437 phosphorylation mediated signaling pathway. Mechanistic studies reveal that MFN2 suppresses mTORC2 through direct interaction by binding its domain HR1. Inhibition of mTORC2 significantly suppresses MFN2 deficient tumor growth. Collectively, this study provides novel insights into the tumor progression associated with MFN2 deficiency and suggests that the importance of mTORC2 inhibitor in the treatment of MFN2 downregulated cancer patients.
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              Anti-Tumor Effects of Mfn2 in Gastric Cancer

              Mitofusin-2 (Mfn2) is a mitochondrial outer membrane protein involved in mitochondrial fusion. Its mutation can cause Charcot-Marie-Tooth disease. Recent studies of Mfn2 in cancer research have not included gastric cancer. We confirmed that Mfn2 expression was lower in tumor tissue than in normal gastric mucosal tissue and that it was negatively correlated with tumor size, indicating an anti-tumor role for Mfn2. In vitro experiments showed that Mfn2 overexpression suppressed gastric cancer cell proliferation and colony formation, weakened the invasion and migratory ability of cancer cells by downregulating MMP-2 and MMP-9, halted the cell cycle and induced apoptosis. Western blotting indicated the likely involvement of P21 and PI3K/Akt signaling. Therefore, Mfn2 is a potential anti-tumor gene and a potential therapeutic target for treating gastric cancer. The progress of gastric cancer may be delayed by controlling Mfn2 expression.
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                Author and article information

                Contributors
                +86 535-6691999 , zhangweiwei1970@163.com
                Journal
                Infect Agent Cancer
                Infect. Agents Cancer
                Infectious Agents and Cancer
                BioMed Central (London )
                1750-9378
                26 November 2018
                26 November 2018
                2018
                : 13
                : 36
                Affiliations
                [1 ]GRID grid.440323.2, Department of Oncology, , The Affiliated Yantai Yuhuangding Hospital of Qingdao University, ; Yantai, Shandong 264000 People’s Republic of China
                [2 ]GRID grid.459626.a, Department of Hepatology, , Infectious Disease Hospital of Yantai City, ; Yantai, Shandong 264001 People’s Republic of China
                Article
                212
                10.1186/s13027-018-0212-7
                6258311
                85cc1fde-d0b5-477d-b157-4851fb9ba20d
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 September 2018
                : 15 November 2018
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                mitofusin-2,prognosis,hepatocellular carcinoma,biomarker
                Oncology & Radiotherapy
                mitofusin-2, prognosis, hepatocellular carcinoma, biomarker

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