Transcription factor Nrf2 induces the up-regulation of lncRNA TUG1 to promote progression and adriamycin resistance in urothelial carcinoma of the bladder

Zhulei Sun, Gui Huang, Hepeng Cheng
Cancer Management and Research 2019, 11: 6079-6090

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.

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