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      The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

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          Abstract

          Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

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          Advances in targeted therapies for hepatocellular carcinoma in the genomic era.

          Josep Llovet, Augusto Villanueva, Anja Lachenmayer … (2015)
          Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.
          Article 0 comments Cited 215 times – based on 0 reviews     Review now
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            MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells.

            Francesca Fornari, Maddalena Milazzo, Pasquale Chieco … (2010)
            MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G(1)-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HCC.
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              Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy.

              Kenji Takahashi, Irene K. Yan, Joseph Wood … (2014)
              Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell-derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses.
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                Author and article information

                Contributors
                Nasha Zhang: wownseva@126.com
                Ming Yang:
                ORCID: http://orcid.org/0000-0003-0310-5839
                86531-67626536 , aaryoung@yeah.net
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 25 October 2019
                Publication date PMC-release: 25 October 2019
                Publication date Collection: 2019
                Volume: 18
                Electronic Location Identifier: 147
                Affiliations
                [1 ]GRID grid.410587.f, Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, , Shandong First Medical University and Shandong Academy of Medical Sciences, ; Jinan, 250117 Shandong Province China
                [2 ]GRID grid.410587.f, Department of Radiation Oncology, Shandong Cancer Hospital and Institute, , Shandong First Medical University and Shandong Academy of Medical Sciences, ; Jinan, 250117 Shandong Province China
                [3 ]GRID grid.410587.f, Department of Intervention Surgery, Shandong Cancer Hospital and Institute, , Shandong First Medical University and Shandong Academy of Medical Sciences, ; Jinan, China
                Author information
                http://orcid.org/0000-0003-0310-5839
                Article
                Publisher ID: 1086
                DOI: 10.1186/s12943-019-1086-z
                PMC ID: 6814027
                PubMed ID: 31651347
                SO-VID: 2e41a04c-bb0a-4b44-8a22-13662839ec87
                Copyright © © The Author(s). 2019
                License:

                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
                Date received : 13 August 2019
                Date accepted : 4 October 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31671300
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: hepatocellular carcinoma,drug resistance,long non-coding rna,microrna
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: hepatocellular carcinoma, drug resistance, long non-coding rna, microrna

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