Long Noncoding RNA Plasmacytoma Variant Translocation 1 Regulates Cisplatin Resistance via miR-3619-5p/TBL1XR1 Axis in Gastric Cancer

Abstract

Background: Chemoresistance greatly hinders the treatment of gastric cancer (GC). Long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been corroborated to be involved in chemoresistance in diverse cancers, including GC. The authors' aim was to investigate the underlying molecular mechanism of PVT1 in cisplatin (DPP) resistance in GC. Methods: Quantitative real-time polymerase chain reaction was conducted to detect the expression levels of PVT1, microRNA (miR)-3619-5p, and transducin beta like 1 x-linked receptor 1 (TBL1XR1) in DDP-resistant GC tissues and cells. 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry assay were used to check cell viability, half inhibition concentration (IC₅₀), and apoptosis, respectively. The abilities of cell migration and invasion were evaluated by transwell assay. The protein levels of drug resistance-related proteins permeability glycoprotein (P-gp), glutathione s-transferase pi (GST-π), multidrug resistance-associated protein, and TBL1XR1 in samples were measured by Western blot. A xenograft tumor model was established to investigate the biological function of PVT1 in vivo. The starBase site was utilized to predict binding sites between miR-3619-5p and PVT1 or TBL1XR1, and the dual-luciferase reporter assay was performed to verify the interaction. Results: The levels of PVT1 and TBL1XR1 were significantly upregulated in DPP-resistant GC tissues and cells, while miR-3619-5p was notably declined. Knockdown of PVT1 enhanced DPP sensitivity of DPP-resistant GC cells. Also, knockdown of PVT1 enhanced the sensitivity of DPP-resistant GC cells to DPP and inhibited tumor growth in vivo. Meanwhile, PVT1 silencing decreased the expression of drug-resistant proteins. Moreover, PVT1 interacted with miR-3619-5p, and TBL1XR1 was a target of miR-3619-5p. Further studies indicated that downregulation of miR-3619-5p transposed PVT1 silencing- or TBL1XR1 silencing-mediated effects on viability, apoptosis, migration, and invasion of DPP-resistant GC cells. Conclusions: PVT1 silencing attenuated the DPP resistance in GC by downregulating TBL1XR1 via sponging miR-3619-5p.

Keywords: DPP; GC; PVT1; TBL1XR1; miR-3619-5p.