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Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis.

ABSTRACT: Gemcitabine is the first-line chemotherapy drug for cholangiocarcinoma (CCA), but acquired resistance has been frequently observed in CCA patients. To search for potential long noncoding RNAs (lncRNAs) involved in gemcitabine resistance, two gemcitabine resistant CCA cell lines were established and dysregulated lncRNAs were identified by lncRNA microarray. Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 expression was closely associated with poor prognosis and chemoresistance of CCA patients. Silencing LINC00665 in gemcitabine resistant CCA cells impaired gemcitabine tolerance, while enforced LINC00665 expression increased gemcitabine resistance of sensitive CCA cells. The gemcitabine resistant CCA cells showed increased EMT and stemness properties, and silencing LINC00665 suppressed sphere formation, migration, invasion and expression of EMT and stemness markers. In addition, Wnt/?-Catenin signaling was activated in gemcitabine resistant CCA cells, but LINC00665 knockdown suppressed Wnt/?-Catenin activation. B-cell CLL/lymphoma 9-like (BCL9L), the nucleus transcriptional regulators of Wnt/?-Catenin signaling, plays a key role in the nucleus translocation of ?-Catenin and promotes ?-Catenin-dependent transcription. In our study, we found that LINC00665 regulated BCL9L expression by acting as a molecular sponge for miR-424-5p. Moreover, silencing BCL9L or miR-424-5p overexpression suppressed gemcitabine resistance, EMT, stemness and Wnt/?-Catenin activation in resistant CCA cells. In conclusion, our results disclosed the important role of LINC00665 in gemcitabine resistance of CCA cells, and provided a new biomarker or therapeutic target for CCA treament.

SUBMITTER: Lu M

PROVIDER: S-EPMC7803957 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis.

Lu Min M Qin Xinglei X Zhou Yajun Y Li Gang G Liu Zhaoyang Z Geng Xiwen X Yue Haodi H

Cell death & disease 20210112 1

Gemcitabine is the first-line chemotherapy drug for cholangiocarcinoma (CCA), but acquired resistance has been frequently observed in CCA patients. To search for potential long noncoding RNAs (lncRNAs) involved in gemcitabine resistance, two gemcitabine resistant CCA cell lines were established and dysregulated lncRNAs were identified by lncRNA microarray. Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 exp ...[more]

PMID: 33436545

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Project description:Purpose:Long intergenic non-coding RNA 922 (LINC00922) plays a critical role in the progression of lung cancer. In this study, we aimed to quantify LINC00922 expression in breast cancer and determine its influence on the malignant behavior of breast cancer cells in vitro and in vivo. We also investigated the mechanism by which LINC00922 affects the progression of breast cancer. Materials and Methods:Reverse transcription-quantitative polymerase chain reaction was performed to quantify LINC00922 expression in breast cancer tissues and cell lines. The cell counting kit-8 assay, flow cytometry, Transwell migration and invasion assays, and tumor model assays were performed to determine the effects of LINC00922 deficiency on breast cancer cell proliferation, apoptosis, migration and invasion in vitro, and tumor growth in vivo, respectively. Furthermore, bioinformatics analysis was performed to predict the potential target microRNA of LINC00922. The prediction was further evaluated using luciferase reporter and RNA immunoprecipitation assays. Results:LINC00922 was clearly overexpressed in breast cancer tissues and cell lines. LINC00922 depletion restricted breast cancer cell proliferation, migration, and invasion but induced cell apoptosis in vitro. Additionally, its knockdown evidently repressed tumor growth of breast cancer cells in vivo. Mechanistically, LINC00922 was demonstrated to serve as a molecular sponge for miR-424-5p in breast cancer cells. Furthermore, brain-derived neurotrophic factor (BDNF) was verified as a direct target of miR-424-5p in breast cancer cells, and BDNF expression was found to be positively regulated by LINC00922 through sponging miR-425-5p. Rescue experiments further revealed that the influences on breast cancer cell proliferation, apoptosis, migration, and invasion induced by LINC00922 silencing were abrogated by increasing the output of the miR-424-5p/BDNF axis. Conclusion:The LINC00922/miR-424-5p/BDNF pathway is implicated in the acceleration of the malignant behavior of breast cancer cells. These findings suggest that this pathway is a promising novel molecular target in breast cancer therapy.

Project description:Background:Exosomes are small membrane vesicles that are secreted by most cell types. Circular RNAs (circRNAs) have recently been identified in exosomes, and exosomal circRNAs exert important biological activities in human cancers, including oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate whether circRNA GDP dissociation inhibitor 2 (circGDI2) was transferred by exosomes and how exosomal circGDI2 regulated OSCC cell malignant behaviors. Methods:The levels of circGDI2, miR-424-5p and suppressor of cancer cell invasion (SCAI) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Transwell assays were performed to detect cell migration and invasion. Measurement of glucose consumption and lactate production were conducted using a corresponding assay kit. Targeted correlations among circGDI2, miR-424-5p and SCAI were confirmed by dual-luciferase reporter assays. Xenograft assays were used to observe the role of circGDI2 in tumor growth in vivo. Results:Our data indicated that circGDI2 was down-regulated in OSCC, and it could be transferred by the exosomes in OSCC cells. The up-regulation of exosomal circGDI2 weakened OSCC cell proliferation, migration, invasion and glycolysis. CircGDI2 functioned as a molecular sponge of miR-424-5p, and SCAI was a direct target of miR-424-5p. MiR-424-5p mediated the repression of exosomal circGDI2 overexpression on OSCC cell malignant behaviors, and miR-424-5p silencing mitigated OSCC cell progression by up-regulating SCAI. Moreover, exosomal circGDI2 regulated SCAI expression through sponging miR-424-5p. Additionally, the overexpression of exosomal circGDI2 inhibited tumor growth in vivo. Conclusion:The present study had led to the identification of exosomal circGDI2 that regulated OSCC cell malignant behaviors through targeting the miR-424-5p/SCAI axis, highlighting circGDI2 as a novel exosome-based cancer biomarker and therapeutic agent for OSCC treatment.

Dataset Information

Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis.

Publications

Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis.

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