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Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair.

ABSTRACT: Corylin, a biologically active agent extracted from Psoralea corylifolia L. (Fabaceae), promotes bone differentiation and inhibits inflammation. Currently, few reports have addressed the biological functions that are regulated by corylin, and to date, no studies have investigated its antitumor activity. In this study, we used cell functional assays to analyze the antitumor activity of corylin in hepatocellular carcinoma (HCC). Furthermore, whole-transcriptome assays were performed to identify the downstream genes that were regulated by corylin, and gain-of-function and loss-of-function experiments were conducted to examine the regulatory roles of the above genes. We found that corylin significantly inhibited the proliferation, migration, and invasion of HCC cells and increased the toxic effects of chemotherapeutic agents against HCC cells. These properties were due to the induction of a long noncoding RNA, RAD51-AS1, which bound to RAD51 mRNA, thereby inhibiting RAD51 protein expression, thus inhibiting the DNA damage repair ability of HCC cells. Animal experiments also showed that a combination treatment with corylin significantly increased the inhibitory effects of the chemotherapeutic agent etoposide (VP16) on tumor growth. These findings indicate that corylin has strong potential as an adjuvant drug in HCC treatment and that corylin can strengthen the therapeutic efficacy of chemotherapy and radiotherapy.

SUBMITTER: Chen CC

PROVIDER: S-EPMC5945779 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair.

Chen Chin-Chuan CC Chen Chi-Yuan CY Ueng Shir-Hwa SH Hsueh Chuen C Yeh Chau-Ting CT Ho Jar-Yi JY Chou Li-Fang LF Wang Tong-Hong TH

Cell death & disease 20180501 5

Corylin, a biologically active agent extracted from Psoralea corylifolia L. (Fabaceae), promotes bone differentiation and inhibits inflammation. Currently, few reports have addressed the biological functions that are regulated by corylin, and to date, no studies have investigated its antitumor activity. In this study, we used cell functional assays to analyze the antitumor activity of corylin in hepatocellular carcinoma (HCC). Furthermore, whole-transcriptome assays were performed to identify th ...[more]

PMID: 29749376

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Project description:OBJECTIVES:The long-noncoding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes in glioblastoma (GBM) tissues. However, the expression pattern and biological function of lncRNAs remain largely unknown. Here, for the first time, the effects of lncRNA lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) on GBM progression both in vitro and in vivo are investigated. MATERIALS AND METHODS:Expression profiles of LEF1-AS1 in GBM specimens were investigated by bioinformatics analyses. LEF1-AS1 expression in GBM tissues was detected using a quantitative polymerase chain reaction. LEF1-AS1 expression was inhibited by transfecting the LEF1-AS1-specific small interfering RNAs (siRNAs) and stable cell lines established were inhibited by transfecting si-LEF1-AS1 viruses. The Cell Counting Kit-8, ethynyl deoxyuridine, and colony formation assay were used to examine proliferation function. The flow cytometry detected cell-cycle change and apoptosis. Migration effects were detected by a Transwell assay. The tumor xenografts and immunohistochemistry were performed to evaluate tumor growth in vivo. RESULTS:In this study, LEF1-AS1 expression was found significantly upregulated in GBM specimens compared with normal tissues. The 5-year overall survival in GBM patients from The Cancer Genome Atlas with high expression of LEF1-AS1 was inferior to that with low expression. It was confirmed that expression of LEF1-AS1 was higher in GBM tissues than normal ones. Knockdown of LEF1-AS1 significantly inhibited the malignancy of GBM cells, including proliferation and invasion, and promoted cell apoptosis. The result of Western blot assays indicated that knockdown of LEF1-AS1-mediated tumor suppression in GBM cells may be via the reduction of ERK and Akt/mTOR signaling activities. Finally, the in vivo experiment also demonstrated that knockdown LEF1-AS1 inhibited the growth-promoting effect of LEF1-AS1 of U87 cells. CONCLUSION:Our result indicated that lncRNA LEF1-AS1 acts as an oncogene in GBM and may be a pivotal target for this disease.

Project description:BackgroundDysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear.MethodsGene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets.ResultsWe showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC.ConclusionsOur study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

Dataset Information

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair.

Publications

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair.

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