Long noncoding RNA TUG1 decreases bladder cancer chemo-sensitivity toward doxorubicin through elevating KPNA2 expression and activating the PI3K/AKT pathway via adsorbing miR-582-5p.

Abstract

Long noncoding RNA taurine-upregulated gene1 (TUG1) has been reported to be implicated in the chemo-resistance of bladder cancer. Hence, this study aimed to survey regulatory mechanism by which TUG1 regulates the chemo-resistance of bladder cancer cells to doxorubicin (DOX). Relative expression of TUG1, miR-582-5p, and karyopherin alpha 2 (KPNA2) was detected by qRT-PCR. The viability and proliferation of DOX-resistant bladder cancer cells were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Protein levels were measured by western blot analysis. The apoptosis, migration, and invasion of DOX-resistant bladder cancer cells were determined by flow cytometry or transwell assays. The relationship between TUG1 or KPNA2 and miR-582-5p was verified by dual-luciferase reporter assay. TUG1 and KPNA2 were upregulated while miR-582-5p was downregulated in resistant bladder cancer tissues and cells. TUG1 inhibition elevated cell chemo-sensitivity, facilitated cell apoptosis, and curbed proliferation, migration, invasion, and autophagy of DOX-resistant bladder cancer cells. Also, TUG1 acted as a sponge for miR-582-5p, and miR-582-5p inhibitor reversed TUG1 knockdown-mediated influence on DOX chemo-sensitivity and malignant behaviors in DOX-resistant bladder cancer cells. Furthermore, miR-582-5p targeted KPNA2, and KPNA2 overexpression counteracted the inhibitory impact of miR-582-5p mimic on DOX chemo-resistance and malignant behaviors in DOX-resistant bladder cancer cells. Additionally, TUG1 silencing inactivated the PI3K/AKT pathway through sponging miR-582-5p. TUG1 sponged miR-582-5p to increase KPNA2 expression and activated the KPNA2/PI3K/AKT pathway, thereby elevating DOX chemo-resistance and malignant behaviors in bladder cancer cells.