Deregulation of UCA1 expression may be involved in the development of chemoresistance to cisplatin in the treatment of non‐small‐cell lung cancer via regulating the signaling pathway of microRNA‐495/NRF2

Abstract

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide.As a platinum-based chemotherapeutic drug, cisplatin has been used for over 30 years in NSCLC treatment while its effects are diminished by drug resistance. Therefore, we aimed to study the potential role of UCA1 in the development of chemoresistance against cisplatin. Real-time polymerase chain reaction, western-blot analysis, and immunofluorescence were used to study the involvement of UCA1, miR-495, and NRF2 in chemoresistance against cisplatin. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the effect of cisplatin on cell proliferation.Computational analysis and luciferase assay were carried out to explore the interaction among UCA1, miR-495, and NRF2. The cisplatin-R group exhibited lower levels of UCA1 and NRF2 expression but a higher level of miR-495 expression than the cisplatin-S group.The growth rate and half-maximal inhibitory concentration of cellular dipeptidyl peptidase (cisplatinum) of the cisplatin-R group were much higher than those in the cisplatin-S group.MiR-495 contained a complementary binding site of UCA1, and the luciferase activity of wild-type UCA1 was significantly reduced after the transfection of miR-495 mimics.MiR-495 directly targeted the 3′-untranslated region (3′-UTR) of NRF2, and the luciferase activity of wild-type NRF2 3′-UTR was evidently inhibited by miR-495 mimics. Finally, UCA1 and NRF2 expressions in the effective group were much lower than that in the ineffective group, along with a much higher level of miR-495 expression. We suggested for the first time that high expression of UCA1 contributed to the development of chemoresistance to cisplatin through the UCA1/miR-495/NRF2 signaling pathway.

LncRNA UCA1 promotes cisplatin resistance in gastric cancer via recruiting EZH2 and activating PI3K/AKT pathway

“…He et al [14] demonstrated that lncRNA UCA1 predicts a poor prognosis and regulates cell proliferation and migration in GC. Besides, UCA1 has been reported to promotes cisplatin resistance in Ovarian Cancer [13], non-small-cell lung cancer [12], oral squamous cell carcinoma [11] and bladder cancer [15], including GC [10]. Furthermore, it is reported that knockdown of UCA1 significantly promoted apoptosis by regulating Bax and cleaved caspase-3/9 expressions [8].…”

“…The caspase family is a protease system that directly causes the decomposition of apoptotic cells, which demonstrates an important role in the network of apoptosis mechanisms [7]. Many researches demonstrated that lncRNA UCA1 associates with the cisplatin resistance in a variety of tumors [10][11][12][13]. LncRNA UCA1, which is capable of controlling the activation of multiple signaling pathways in cancers, has been extensively researched in many tumors, including GC [10][11][12][13][14][15].…”

The role of non-coding RNAs in chemotherapy for gastrointestinal cancers

“…398,399 He et al 400 reported that UCA1 expression could predict a poor prognosis in patients, and it could also modulate GC cell migration and proliferation in vitro. It was also reported that UCA1 could increase cisplatin resistance in ovarian cancer, 401 non-small cell lung cancer, 402 oral squamous cell carcinoma, 403 bladder cancer, 404 and GC. 405 UCA1 knockdown was reported to increase apoptosis by modulating the expression of Bax and cleaved caspase-3/9.…”

Mechanistic study of lncRNA UCA1 promoting growth and cisplatin resistance in lung adenocarcinoma

“…UCA1/miRNA204-5p/cAMP responsive element binding protein-1 (CREB1) axis [ 17 ], UCA1/miRNA-143/Fos-like antigen 2 (FOSL2) axis [ 18 ], and UCA1/miRNA-196a-5p/CREB axis [ 19 ] were involved in enhancing the chemoresistance of colorectal, ovarian, and bladder cancers. In NSCLC, Li et al [ 20 ] discovered complementary binding sites between UCA1 and miRNA-495, and indicated that UCA1 promoted cisplatin resistance of NSCLC by regulating the miRNA-495/Nuclear factor-erythroid 2-related factor 2 (NRF2) axis as ceRNA. Liu et al [ 21 ] found that epithelial–mesenchymal transition (EMT) related proteins had changed and LUAD cell lines restored the sensitivity of cisplatin after UCA1 knockdown, which meant that UCA1 promoted cisplatin resistance by participating in the EMT signaling pathway.…”