Dataset Information

Downregulation of exosomal miR?1273a increases cisplatin resistance of non?small cell lung cancer by upregulating the expression of syndecan binding protein.

ABSTRACT: Resistance to platinum?based drugs, such as cisplatin (CDDP), has been one of the major factors adversely affecting the clinical prognosis of patients with advanced non?small cell lung cancer (NSCLC). While it has been demonstrated that dysregulation of microRNAs (miRNAs) may contribute to cisplatin resistance in NSCLC, the underlying mechanisms remain largely unclear. In the present study, the effect of exosomal miR?1273a on cisplatin sensitivity of NSCLC was investigated. Microarray analysis was conducted to analyze the miRNA expression profiles in exosomes isolated from A549 cells treated with or without CDDP, and miR?1273a was found to be the most prominently downregulated miRNA in CDDP?treated exosomes. Overexpression of miR?1273a significantly increased the cytotoxicity of CDDP and induced apoptosis in A549 cells. Syndecan binding protein (SDCBP) was predicted to be a direct target of miR?1273a by bioinformatics and was found to be downregulated by miR?1273a in A549 cells. Furthermore, decreased plasma exosomal miR?1273a and increased plasma SDCBP levels were found to be associated with worse therapeutic outcomes of patients with advanced NSCLC receiving platinum?based chemotherapy. These findings suggest that miR?1273a is closely associated with the development of cisplatin resistance and may serve as a potential prognostic biomarker and therapeutic target for NSCLC.

SUBMITTER: Zhao X

PROVIDER: S-EPMC7551135 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Downregulation of exosomal miR‑1273a increases cisplatin resistance of non‑small cell lung cancer by upregulating the expression of syndecan binding protein.

Zhao Xiaolong X Li Mengxia M Dai Xiaoyan X Yang Yuyin Y Peng Yang Y Xu Chengxiong C Dai Nan N Wang Dong D

Oncology reports 20200904 5

Resistance to platinum‑based drugs, such as cisplatin (CDDP), has been one of the major factors adversely affecting the clinical prognosis of patients with advanced non‑small cell lung cancer (NSCLC). While it has been demonstrated that dysregulation of microRNAs (miRNAs) may contribute to cisplatin resistance in NSCLC, the underlying mechanisms remain largely unclear. In the present study, the effect of exosomal miR‑1273a on cisplatin sensitivity of NSCLC was investigated. Microarray analysis w ...[more]

PMID: 32901857

Similar Datasets

Project description:BackgroundLINC00173 had been reported as a cisplatin (cis-diamminedichloroplatinum, DDP) chemotherapy-resistant inducer in small-cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). This study aimed to display reverse data for LINC00173 as a DDP chemosensitivity-inducing factor in lung adenocarcinoma (LUAD).MethodsLINC00173 was screened from the Gene Expression Omnibus database (GSE43493). The expression level of LINC00173 in LUAD tissues and cell lines was detected using in situ hybridization and quantitative reverse transcription-polymerase chain reaction. Colony formation, cell viability, half-maximal inhibitory concentration, flow cytometry, and xenograft mouse model were used to evaluate the role of LINC00173 in the chemosensitivity of LUAD to DDP. The mechanism of LINC00173 in DDP resistance by mediating miR-1275/PROCA1/ZFP36L2 axis to impair BCL2 mRNA stability was applied, and co-immunoprecipitation, chromatin immunoprecipitation, RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays were performed.ResultsLINC00173 downregulation in patients with DDP-resistant LUAD was correlated with poor prognosis. Further, LINC00173 expression was significantly reduced in DDP-resistant LUAD cells and DDP-treated human LUAD tissues. Suppressed LINC00173 expression in LUAD cells enhanced DDP chemoresistance in vivo and in vitro, while restored LINC00173 expression in DDP-resistant LUAD cells markedly regained chemosensitivity to DDP. Mechanistically, DDP-resistant LUAD cells activated PI3K/AKT signal and further elevated the c-Myc expression. The c-Myc, as an oncogenic transcriptional factor, bound to the promoter of LINC00173 and suppressed its expression. The reduced LINC00173 expression attenuated the adsorption of oncogenic miR-1275, downregulating the expression of miR-1275 target gene PROCA1. PROCA1 played a potential tumor-suppressive role inducing cell apoptosis and DDP chemosensitivity via recruiting ZFP36L2 to bind to the 3' untranslated region of BCL2, reducing the stability of BCL2 mRNA and thus activating the apoptotic signal.ConclusionsThis study demonstrated a novel and critical role of LINC00173. It was transcriptionally repressed by DDP-activated PI3K/AKT/c-Myc signal in LUAD, promoting DDP-acquired chemotherapeutic resistance by regulating miR-1275 to suppress PROCA1/ZFP36L2-induced BCL2 degradation, which led to apoptotic signal reduction. These data were not consistent with the previously described role of LINC00173 in SCLC or LUSC, which suggested that LINC00173 could play fine-tuned DDP resistance roles in different pathological subtypes of lung cancer. This study demonstrated that the diminished expression of LINC00173 might serve as an indicator of DDP-acquired resistance in LUAD.

Project description:BackgroundsAs previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms.MethodsWe performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues.ResultsThe cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3' untranslated region (3'UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells.ConclusionsTaken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.

Dataset Information

Downregulation of exosomal miR?1273a increases cisplatin resistance of non?small cell lung cancer by upregulating the expression of syndecan binding protein.

Publications

Downregulation of exosomal miR‑1273a increases cisplatin resistance of non‑small cell lung cancer by upregulating the expression of syndecan binding protein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets