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Long noncoding RNA CEBPA-DT promotes cisplatin chemo-resistance through CEBPA/BCL2 mediated apoptosis in oral squamous cellular cancer.

ABSTRACT: Intrinsic or developing resistance to chemotherapy drugs including cisplatin (CDDP) remains the major limitation of cancer therapeutic efficacy in cancers. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in cisplatin resistance is poorly understood. Here, we found that the expression of lncRNA CEBPA-DT/CEBPA/BCL2 was upregulated in cisplatin resistance OSCC cells (Cal27-CisR and HSC4-CisR) compared with their parental cells (Cal27 and HSC4). CEBPA-DT overexpression could upregulated both cytoplasmic and nuclear CEBPA expression. Down-regulation of CEBPA-DT enhances cisplatin sensitivity, facilitates cell apoptosis in cisplatin-resistant OSCC cells. In addition, we identified that CEBPA-DT regulates cisplatin chemosensitivity through CEBPA/BCL2-mediated cell apoptosis. Knockdown of CEBPA and BCL2 could alleviate the increasement of cisplatin resistance induced by CEBPA-DT overexpression. Our findings indicate that downregulation of lncRNA CEBPA-DT may be a potential therapy to overcome cisplatin resistance in OSCC.

SUBMITTER: Qiao X

PROVIDER: S-EPMC8579301 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Long noncoding RNA CEBPA-DT promotes cisplatin chemo-resistance through CEBPA/BCL2 mediated apoptosis in oral squamous cellular cancer.

Qiao Xue X Liu Jiayi J Zhu Li L Song Rongbo R Zhong Ming M Guo Yan Y

International journal of medical sciences 20210927 16

Intrinsic or developing resistance to chemotherapy drugs including cisplatin (CDDP) remains the major limitation of cancer therapeutic efficacy in cancers. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in cisplatin resistance is poorly understood. Here, we found that the expression of lncRNA CEBPA-DT/CEBPA/BCL2 was upre ...[more]

PMID: 34790046

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Project description:BackgroundHepatocellular carcinoma (HCC) is the world's third leading cause of cancer-related death; due to the fast growth and high prevalence of tumor recurrence, the prognosis of HCC patients remains dismal. Long non-coding RNA CEBPA-DT, a divergent transcript of the CCAAT Enhancer Binding Protein Alpha (CEBPA) gene, has been shown to participate in multiple tumor progression. However, no research has established its cancer-promoting mechanism in HCC yet.MethodsCEBPA-DT was identified in human HCC tissues through RNA sequencing. The expression level of CEBPA-DT was assessed by quantitative real-time PCR. The biological effects of CEBPA-DT were evaluated in vitro and in vivo through gain or loss of function experiments. RNA fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were applied to investigate the downstream target of CEBPA-DT. Immunofluorescence, subcellular protein fractionation, western blot, and co-immunoprecipitation were performed to analyze the subcellular location of β-catenin and its interaction with Discoidin domain-containing receptor 2 (DDR2).ResultsCEBPA-DT was upregulated in human HCC tissues with postoperative distant metastasis and intimately related to the worse prognosis of HCC patients. Silencing of CEBPA-DT inhibited the growth, migration and invasion of hepatoma cells in vitro and in vivo, while enhancement of CEBPA-DT played a contrasting role. Mechanistic investigations demonstrated that CEBPA-DT could bind to heterogeneous nuclear ribonucleoprotein C (hnRNPC), which facilitated cytoplasmic translocation of hnRNPC, enhanced the interaction between hnRNPC and DDR2 mRNA, subsequently promoted the expression of DDR2. Meanwhile, CEBPA-DT induced epithelial-mesenchymal transition (EMT) process through upregulation of Snail1 via facilitating nuclear translocation of β-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and β-catenin, thus promoting the nuclear translocation of β-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis.ConclusionsOur results suggested that CEBPA-DT promoted HCC metastasis through DDR2/β-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/β-catenin axis may be used as a potential therapeutic target for HCC treatment.

Dataset Information

Long noncoding RNA CEBPA-DT promotes cisplatin chemo-resistance through CEBPA/BCL2 mediated apoptosis in oral squamous cellular cancer.

Publications

Long noncoding RNA CEBPA-DT promotes cisplatin chemo-resistance through CEBPA/BCL2 mediated apoptosis in oral squamous cellular cancer.

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