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TP53TG1 enhances cisplatin sensitivity of non-small cell lung cancer cells through regulating miR-18a/PTEN axis.

ABSTRACT: Background:The acquisition of drug resistance has been considered as a main obstacle for cancer chemotherapy. Tumor protein 53 target gene 1 (TP53TG1), a p53-induced lncRNA, plays a vital role in the progression of human cancers. However, little is known about the detailed function and molecular mechanism of TP53TG1 in cisplatin resistance of NSCLC. Methods:qRT-PCR analysis was used to detect the expression of TP53TG1, miR-18a and PTEN mRNA in NSCLC tissues and cells. Western blot analysis was performed to determine the protein level of PTEN and cleaved caspase-3. Cell viability and IC50 value were measured by MTT assay. Cell apoptosis was confirmed by flow cytometry assay. Subcellular fractionation assay was used to identify the subcellular location of TP53TG1. Dual-luciferase reporter assay, RNA pull down assay and RNA immunoprecipitation assay were carried out to verify the interaction between TP53TG1 and miR-18a. Xenografts in nude mice were established to verify the effect of TP53TG1 on cisplatin sensitivity of NSCLC cells in vivo. Results:TP53TG1 level was downregulated in NSCLC tissues and cell lines. Upregulated TP53TG1 enhanced cisplatin sensitivity and apoptosis of A549/DDP cells, while TP53TG1 depletion inhibited cisplatin sensitivity and apoptosis of A549 cells. TP53TG1 suppressed miR-18a expression in A549 cells. Moreover, TP53TG1-mediated enhancement effect on cisplatin sensitivity was abated following the restoration of miR-18a expression in A549/DDP cells, while si-TP53TG1-induced decrease of cisplatin sensitivity and apoptosis was counteracted by miR-18a inhibitor in A549 cells. Furthermore, TP53TG1 promoted PTEN expression via inhibiting miR-18a. Finally, TP53TG1 sensitized NSCLC cells to cisplatin in vivo. Conclusion:TP53TG1 increased the sensitivity of NSCLC cells to cisplatin by modulating miR-18a/PTEN axis, elucidating a novel approach to boost the effectiveness of chemotherapy for NSCLC.

SUBMITTER: Xiao H

PROVIDER: S-EPMC5863826 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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TP53TG1 enhances cisplatin sensitivity of non-small cell lung cancer cells through regulating miR-18a/PTEN axis.

Xiao Huijuan H Liu Yihe Y Liang Pan P Wang Bo B Tan Hongna H Zhang Yonggao Y Gao Xianzheng X Gao Jianbo J

Cell & bioscience 20180322

<h4>Background</h4>The acquisition of drug resistance has been considered as a main obstacle for cancer chemotherapy. Tumor protein 53 target gene 1 (TP53TG1), a p53-induced lncRNA, plays a vital role in the progression of human cancers. However, little is known about the detailed function and molecular mechanism of TP53TG1 in cisplatin resistance of NSCLC.<h4>Methods</h4>qRT-PCR analysis was used to detect the expression of TP53TG1, miR-18a and PTEN mRNA in NSCLC tissues and cells. Western blot ...[more]

PMID: 29588850

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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.

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TP53TG1 enhances cisplatin sensitivity of non-small cell lung cancer cells through regulating miR-18a/PTEN axis.

Publications

TP53TG1 enhances cisplatin sensitivity of non-small cell lung cancer cells through regulating miR-18a/PTEN axis.

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