Abstract
BackgroundThe 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.MethodsqRT-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.ResultsTP53TG1 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.ConclusionTP53TG1 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.
Highlights
The acquisition of drug resistance has been considered as a main obstacle for cancer chemotherapy
Down‐regulation of Tumor protein 53 target gene 1 (TP53TG1) in Non-small cell lung cancer (NSCLC) tissues and cell lines To explore the effect of TP53TG1 on NSCLC, the level of TP53TG1 was firstly detected in 40 pairs of NSCLC tissues and adjacent, histologically normal tissues by qRTPCR assay and normalized to Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
The results presented that TP53TG1 level was strikingly decreased in NSCLC cell lines compared with normal bronchial epithelial cells HBE (Fig. 1c)
Summary
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. An increasing number of lncRNAs have been reported to be associated with NSCLC progression [7]. Maternally expressed gene 3 (MEG3) expression was downregulated in DDP-resistant lung cancer cells, and MEG3 overexpression contributed to increased cisplatin chemosensitivity through regulating p53- and Bcl-xl-induced mitochondria apoptosis pathway [11]. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) induced DDP resistance by functioning as a ceRNA of miR-101 to regulate the expression of SOX9 and downstream Wnt signaling [12]. Tumor protein 53 target gene 1 (TP53TG1, GenBank Accession Number NM_007233), a long intergenic non-protein-coding RNA with 751 nt in length, was revealed to exert a tumor-suppressor feature in human cancer [13]. Little is known about the detailed function and molecular mechanism of TP53TG1 on cisplatin resistance of NSCLC
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