Background: Taurine-upregulated gene 1  (TUG1 ) has been documented to be implicated in carcinogenesis and chemoresistance in solid tumors. Here, we explored the biological role and regulatory mechanism of TUG1  in progression and chemoresistance of urothelial carcinoma of the bladder (UCB).
Methods: Nuclear factor-erythroid 2  (NF-E2 )-related factor 2  (Nrf2 ) mRNA and TUG1  expression was determined by quantitative reverse transcription polymerase chain reaction. Western blot was performed to determine the protein levels of Nrf2, p-glycoprotein (p-gp), Ki-67 (Ki67), matrix metalloproteinase (MMP)-2 and MMP-9 and cleaved caspase-3. The effects of either Nrf2  or TUG1  knockdown on the proliferation, invasion, apoptosis and adriamycin (ADM) resistance of UCB cells were evaluated by CCK-8 assay, transwell invasion assay and flow cytometry analysis. Xenograft tumor assay was carried out to confirm the role of Nrf2  and TUG1  in ADM resistance of UCB cells in vivo.
Results: Nrf2  and TUG1  were upregulated in UCB tissues and cell lines. A positive correlation between Nrf2  and TUG1  expression was discovered in UCB tissues. Moreover, Nrf2  and TUG1  expression levels were higher in ADM-resistant cells compared with those in parental cells. Furthermore, Nrf2  positively regulated the expression of TUG1  in UCB cells. Knockdown of either Nrf2  or TUG1  led to the inhibition of cell proliferation and invasion and promotion of cell apoptosis, accompanying with down-regulation of Ki67, MMP-2 and MMP-9 and up-regulation of cleaved caspase-3. Knockdown of either Nrf2  or TUG1  enhanced the sensitivity of BIU-87/ADM and T24/ADM cells to ADM, as indicated by decreased expression of p-gp. Besides, knockdown of either Nrf2  or TUG1  inhibited tumor growth in the absence or presence of ADM in vivo.
Conclusions: Nrf2  induces the up-regulation of TUG1  to promote progression and ADM resistance in UCB.
Keywords: urothelial carcinoma of the bladder, nuclear factor-erythroid 2  (NF-E2 )-related factor 2 , taurine-upregulated gene 1 , Adriamycin