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CircRNA DONSON contributes to cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis.

ABSTRACT: Background:Circular RNA downstream neighbor of SON (circDONSON) has been revealed to promote gastric cancer (GC) growth and invasion, while the role and molecular mechanism underlying circDONSON in GC cisplatin (DDP) resistance remain unclear. Methods:Levels of circDONSON, microRNA (miR)-802, and B lymphoma Mo-MLV insertion region 1 (BMI1) mRNA were detected using quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit-8 assay, colony formation assay and flow cytometry, respectively. Protein levels of BMI1, Cyclin D1, p27, Caspase-3 Cleavage and Caspase-9 Cleavage were determined by western blot. The interaction between miR-802 and circDONSON or BMI1 was confirmed by dual-luciferase reporter assay. In vivo experiments were conducted via the murine xenograft model. Results:CircDONSON was elevated in GC tissues and cell lines, especially in DDP-resistant GC tissues and cells. Knockdown of circDONSON sensitized GC cells to DDP by inhibiting cell viability and promoting cell apoptosis in vitro. Further mechanism-related investigations suggested that circDONSON functioned as "sponge" by competing for miR-802 binding to modulate its target BMI1. Silencing miR-802 reversed the inhibition of DDP-resistance in GC cells induced by circDONSON down-regulation. Besides, miR-802 alleviated DDP resistance in GC cells by targeting BMI1. Functionally, circDONSON knockdown enhanced the cytotoxicity of DDP in GC in vivo. Conclusion:Our findings demonstrated circDONSON promoted cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis, shedding light on the development of a novel therapeutic strategy to overcome chemoresistance in gastric cancer patients.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7310092 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CircRNA DONSON contributes to cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis.

Liu Yong Y Xu Jianzhong J Jiang Min M Ni Lingna L Ling Yang Y

Cancer cell international 20200622

<h4>Background</h4>Circular RNA downstream neighbor of SON (circDONSON) has been revealed to promote gastric cancer (GC) growth and invasion, while the role and molecular mechanism underlying circDONSON in GC cisplatin (DDP) resistance remain unclear.<h4>Methods</h4>Levels of circDONSON, microRNA (miR)-802, and B lymphoma Mo-MLV insertion region 1 (BMI1) mRNA were detected using quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit-8 as ...[more]

PMID: 32581651

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Project description:BackgroundCisplatin (DDP) is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and long-term DDP stimulation increased resistance of NSCLC cells to this drug by enriching cancer stem cells (CSCs), which contributed to recurrence and worse prognosis of NSCLC, but the molecular mechanisms are still not fully delineated.MethodsReal-Time qPCR and Western Blot analysis were conducted to examine gene expressions at mRNA and protein levels, respectively. Dual-luciferase reporter gene system was used to validate the targeting sites among circRNA CDR1as, miR-641 and HOXA9 mRNA. Cell growth was evaluated by CCK-8 assay, trypan blue staining assay and colony formation assay. The Annexin V-FITC/PI double staining method was employed to measure cell apoptosis ratio. Spheroid formation and flow cytometer assay was used to evaluate cell stemness. Xenograft mice models were established to measure tumorgenicity in vivo, and Ki67 expressions in mice tumor tissues were examined by immunohistochemistry (IHC).ResultsHere we identified a novel circRNA CDR1as/miR-641/Homeobox protein Hox-A9 (HOXA9) pathway regulated stemness and DDP chemoresistance in NSCLC. Mechanistically, circRNA CDR1as and HOXA9 were high-expressed, while miR-641 was low-expressed in DDP-resistant NSCLC cells, instead of their corresponding parental DDP-sensitive NSCLC cells. Additionally, we validated that circRNA CDR1as positively regulated HOXA9 in NSCLC cells by serving as an RNA sponge for miR-641, and knock-down of circRNA CDR1as increased the sensitivity of DDP-resistant NSCLC cells, which were reversed by downregulating miR-641 and upregulating HOXA9. Consistently, overexpression of circRNA CDR1as increased drug resistance of DDP-sensitive NSCLC cells by regulating miR-641/HOXA9 axis. In addition, the expression levels of stemness signatures (SOX2, OCT4 and Nanog) were higher in DDP-resistant NSCLC cells, which also tended to form spheres and enrich CD44+CD166+ population compared to their parental DDP-sensitive NSCLC cells, suggesting that CSCs were enriched in DDP-resistant NSCLC cells. Notably, knock-down of circRNA CDR1as inhibited stemness of DDP-resistant NSCLC cells by inhibiting HOXA9 through upregulating miR-641.ConclusionsTaken together, this study identified that circRNA CDR1as regulated stemness and DDP chemoresistance in NSCLC cells by targeting miR-641/HOXA9 axis.

Dataset Information

CircRNA DONSON contributes to cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis.

Publications

CircRNA DONSON contributes to cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis.

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