Dataset Information

The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/?-Catenin Signaling Pathway.

ABSTRACT: Drug resistance, including adriamycin (ADR)-based therapeutic resistance, is a crucial cause of chemotherapy failure in breast cancer treatment. Acquired chemoresistance has been identified to be closely associated with the overexpression of P-glycoprotein (P-gp/ABCB1). Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) can be involved in carcinogenesis; however, its roles in ABCB1-mediated ADR resistance are poorly understood. In this study, we identified a panel of differentially expressed lncRNAs, mRNAs, and microRNAs (miRNAs) in MCF-7 and MCF-7/ADR cell lines through RNA sequencing (RNA-seq) technologies. GAS5 level was downregulated whereas ABCB1 level was upregulated in the resistant breast cancer tissues and cells. Overexpression of GAS5 significantly enhanced the ADR sensitivity and apoptosis, and it inhibited the efflux function and expression of ABCB1 in vitro, while knockdown of GAS5 had the opposite effects. Further mechanism-related investigations indicated that GAS5 acted as an endogenous "sponge" by competing for miR-221-3p binding to regulate its target dickkopf 2 (DKK2), and then it inhibited the activation of the Wnt/?-catenin pathway. Functionally, GAS5 enhanced the anti-tumor effect of ADR in vivo. Collectively, our findings reveal that GAS5 exerted regulatory function in ADR resistance possibly through the miR-221-3p/DKK2 axis, providing a novel approach to develop promising therapeutic strategy for overcoming chemoresistance in breast cancer patients.

SUBMITTER: Chen Z

PROVIDER: S-EPMC7056627 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/β-Catenin Signaling Pathway.

Chen Zhaolin Z Pan Tingting T Jiang Duochen D Jin Le L Geng Yadi Y Feng Xiaojun X Shen Aizong A Zhang Lei L

Molecular therapy. Nucleic acids 20200201

Drug resistance, including adriamycin (ADR)-based therapeutic resistance, is a crucial cause of chemotherapy failure in breast cancer treatment. Acquired chemoresistance has been identified to be closely associated with the overexpression of P-glycoprotein (P-gp/ABCB1). Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) can be involved in carcinogenesis; however, its roles in ABCB1-mediated ADR resistance are poorly understood. In this study, we identified a panel of differentially exp ...[more]

PMID: 32160712

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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses a spectrum of diseases, including chronic obstructive bronchitis and emphysema. Pyroptosis is a unique form of inflammatory cell death mediated by the activation of caspase‑1 and inflammasomes. The long non‑coding RNA (lncRNA) growth arrest‑specific 5 (GAS5) is a well‑documented tumor suppressor, which is associated with cell proliferation and death in various diseases. The aim of the present study was to evaluate whether lncRNA GAS5 is associated with the pyroptosis in COPD. To create a COPD cell model, MRC‑5 cells were treated with 10 µg/ml lipopolysaccharide (LPS) for 48 h. Then the level of pro‑caspase 1, caspase 1, IL‑1β, IL‑18, NLRP3 and cleaved gasdermin D (GSDMD) was examined by western blotting. GAS5 mRNA level was detected by qualitative PCR following LPS treatment in MRC‑5 cells. Subsequently, IL‑2, IL‑6, IL‑10 and TNF‑α in MRC‑5 cells was measured by ELISA. Then the proliferation ability of MRC‑5 cells was detected by CCK‑8. Cell death was detected by TUNEL assay. LDH release was measured using an LDH Cytotoxicity Assay kit. The Magna RIP kit was used to validate the interaction between GAS5 and miR‑223‑3p. The present study revealed that increased expression levels of caspase‑1, IL‑1β, IL‑18 and cleaved GSDMD were observed in LPS‑treated MRC‑5 cells, indicating that pyroptosis is involved in COPD progression. Additionally, LPS induced the increase in GAS5 mRNA expression levels and the release of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α), suggesting that GAS5 is implicated in pyroptosis in COPD. Furthermore, upregulation of GAS5 promoted cell death and inhibited proliferation in the MRC‑5 cell line. Additionally, increased GAS5 expression significantly promoted the production of caspase‑1, IL‑1β, IL‑18, cleaved GSDMD and NLR pyrin domain containing protein 3 (NLRP3). A dual‑luciferase assay demonstrated that GAS5 could directly bind to microRNA‑223‑3p (miR‑223‑3p), and NLRP3 is a direct target of miR‑223‑3p. Furthermore, GAS5 reduced the expression levels of miR‑223‑3p, while it increased the expression levels of NLRP3. The present study concluded that lncRNA GAS5 promoted pyroptosis in COPD by targeting the miR‑223‑3p/NLRP3 axis, implying that GAS5 could be a potential target for COPD.

Dataset Information

The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/?-Catenin Signaling Pathway.

Publications

The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/β-Catenin Signaling Pathway.

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