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      MicroRNA-155-3p promotes hepatocellular carcinoma formation by suppressing FBXW7 expression

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          Abstract

          Background

          MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignant tumors. In the present study, we analyzed the role miR-155-3p plays in Hepatocellular carcinoma (HCC), which has been reported participation in some other types of cancer.

          Methods

          qRT-PCR was used to measure the levels of miR-155-3p in HCC specimens and HCC cell lines. Overexpression of miR-155-3p and miR-155-3p inhibitor were transfected into HCC cell lines to investigate its role in HCC. Colony formation assay and 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays were used to analyses cell proliferation in vitro. In vivo tumor formation assays were performed in BALB/c nude mice. Luciferase reporter assay was carried out to measure the translation of F-Box and WD repeat romain containing 7 (FBXW7).

          Results

          We found that miR-155-3p was remarkably upregulated both in HCC tissue and cell lines. Overexpression of miR-155-3p enhanced HCC cell proliferation in vitro and tumorigenesis in vivo. In addition, overexpression of miR-155-3p is correlated with decreased levels FBXW7 mainly through inhibiting the expression of FBXW7.

          Conclusions

          Our studies suggest that miR-155-3p plays an important role in the pathogenesis of HCC and implicates its potential applications in the treatment of HCC cancer.

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          Most cited references24

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          Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics

          Hepatocellular carcinoma (HCC) is a common malignancy in developing countries and its incidence is on the rise in the developing world. The epidemiology of this cancer is unique since its risk factors, including hepatitis C and B, have been clearly established. The current trends in the shifting incidence of HCC in different regions of the world can be explained partly by the changing prevalence of hepatitis. Early detection offers the only hope for curative treatment for patients with HCC, hence effective screening strategies for high-risk patients is of utmost importance. Liver transplantation and surgical resection remains the cornerstone of curative treatment. But major advances in locoregional therapies and molecular-targeted therapies for the treatment of advanced HCC have occurred recently. In this review, current trends in the worldwide epidemiology, surveillance, diagnosis, standard treatments, and the emerging therapies for HCC are discussed.
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            CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.

            The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.
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              MicroRNA-331-3p promotes proliferation and metastasis of hepatocellular carcinoma by targeting PH domain and leucine-rich repeat protein phosphatase.

              Hepatocellular carcinoma (HCC) is a highly invasive tumor with frequent intrahepatic or pulmonary metastasis, which is the main reason for high recurrence and poor survival of HCC after liver resection. However, the mechanisms for metastasis remain incompletely clear. Given that microRNAs (miRNAs) are implicated in HCC progression, we explored a potential role of miRNAs in metastasis by performing miRNA expression profiling in three subtypes of HCC with different metastatic potentials. We discovered miR-331-3p as one of most significantly overexpressed miRNAs and highly associated with metastasis of HCC. Increased expression of miR-331-3p was correlated with poor long-term survival of HCC. We provided both in vivo and in vitro evidence demonstrating that miR-331-3p promoted proliferation and metastasis of HCC cells. Using an integrated approach, we uncovered that PH domain and leucine-rich repeat protein phosphatase (PHLPP) was a novel target of miR-331-3p. Indeed, the miR-331-3p-mediated effects were antagonized by reexpression of PHLPP or mimicked by silencing of PHLPP. We further showed that miR-331-3p-mediated inhibition of PHLPP resulted in stimulation of protein kinase B (AKT) and subsequent epithelial mesenchymal transition (EMT). Finally, inhibition of miR-331-3p through a jetPEI-mediated delivery of anti-miR-331-3p vector resulted in marked inhibition of proliferation and metastasis of HCC in xenograft mice. miR-331-3p promotes proliferation and EMT-mediated metastasis of HCC through suppression of PHLPP-mediated dephosphorylation of AKT. Our work implicates miR-331-3p as a potential prognostic biomarker and a novel therapeutic target. © 2014 by the American Association for the Study of Liver Diseases.
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                Author and article information

                Contributors
                tangbtg@126.com
                biaoleidoc@sina.com
                guangyingqitg@163.com
                xingsiliangtg@sina.com
                fangtangdoctor@163.com
                shengguangyuantg@163.com
                zhenranwangtg@sina.com
                shuipingyudoct@163.com
                +86.0773.2809503 , +86.0773.2809503 , hesongqingdoc@126.com
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                16 June 2016
                16 June 2016
                2016
                : 35
                : 93
                Affiliations
                [ ]Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, 541001 Guangxi People’s Republic of China
                [ ]Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, 541001 Guangxi People’s Republic of China
                [ ]Department of Pathology and Physiopathology, Guilin Medical University, Guilin, 541004 Guangxi People’s Republic of China
                Article
                371
                10.1186/s13046-016-0371-6
                4910248
                27306418
                09162ac3-9937-413b-ae69-523b6ec3b820
                © The Author(s). 2016

                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
                : 26 March 2016
                : 7 June 2016
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                fbxw7,hepatocellular carcinoma,mir-155-3p
                Oncology & Radiotherapy
                fbxw7, hepatocellular carcinoma, mir-155-3p

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