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      Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling

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          Abstract

          Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.

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          Most cited references 36

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          The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489.

          Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years.
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            Critical role of miR-10b in transforming growth factor-β1-induced epithelial-mesenchymal transition in breast cancer.

            Epithelial-mesenchymal transition (EMT) is a key process in the tumor metastatic cascade that is characterized by the loss of cell-cell junctions and cell polarity, resulting in the acquisition of migratory and invasive properties. Recent evidence showed that altered microRNA-10b (miR-10b) expression was implicated in the occurrence of EMT of breast cancer. However, the exact role and underlying mechanisms of miR-10b in the EMT of breast cancer still remain unknown. In this study, miR-10b was found to be upregulated in breast cancer tissues and breast cancer cell lines and the expression of miR-10b was shown to be closely correlated with aggressiveness in breast cancer. Treating breast cancer cells with the miR-10b inhibitor increased E-cadherin expression while decreasing vimentin expression. At the same time, on inhibition of miR-10b, the invasion and proliferation ability of breast cancer cells also decreased. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that induces EMT in multiple cell types. Here, we identified miR-10b as a target gene of TGF-β1. The expression of miR-10b increased during TGF-β1-induced EMT of breast cancer cells. Further study showed that inhibition of miR-10b expression partially reversed the EMT, invasion and proliferation induced by TGF-β1 in breast cancer cells. Taken together, these results demonstrated a novel function for miR-10b in TGF-β1-induced EMT in breast cancer and increased their metastatic potential. MiR-10b might become a possible target for gene therapy in breast cancer.
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              Epidemiology of gynecologic cancers in China

              Cancer has become a major disease burden across the globe. It was estimated that 4.29 million new incident cases and 2.81 million death cases of cancer would occur in 2015 in China, with the age-standardized incidence rate (ASIR) of 201.1 per 100,000 and age-standardized mortality rate (ASMR) of 126.9 per 100,000, respectively. For females, 2 of the top 10 most common types of cancer would be gynecologic cancers, with breast cancer being the most prevalent (268.6 thousand new incident cases) and cervical cancer being the 7th most common cancer (98.9 thousand new incident cases). The incidence and mortality of gynecologic cancers have been constantly increasing in China over last 2 decades, which become a major health concern for women. Survival rates of gynecologic cancers are generally not satisfactory and decrease along with advancing stage, though national data on survival are still not available. It is of great importance to overview on the epidemiology of gynecologic cancers, which may provide scientific clues for strategy-making of prevention and control, and eventually lowering the incidence and mortality rate as well as improving the survival rate in the future.
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                Author and article information

                Contributors
                zhjcc@yahoo.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                8 September 2020
                8 September 2020
                2020
                : 10
                Affiliations
                [1 ]GRID grid.452829.0, Department of Obstetrics & Gynecology, , The Second Hospital of Jilin University, ; 218 Ziqiang Street, Changchun, 130041 Jilin China
                [2 ]GRID grid.64924.3d, ISNI 0000 0004 1760 5735, Jilin University, ; Changchun, Jilin China
                Article
                71153
                10.1038/s41598-020-71153-0
                7478977
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Jilin University (JLU)
                Award ID: 201910183599
                Funded by: Department of Finance of Jilin Province (Jilin Provincial Department of Finance)
                Award ID: 2019SCZ704
                Funded by: Jilin province development and reform commission
                Award ID: 2019C051-7
                Award Recipient :
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                © The Author(s) 2020

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                ovarian cancer, long non-coding rnas

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