Image_3_Reduction of Bladder Cancer Chemosensitivity Induced by the Effect of HOXA-AS3 as a ceRNA for miR-455-5p That Upregulates Notch1.tif
Chemoresistance is one of the main causes of recurrence in bladder cancer patients and leads to poor prognosis. Recently, long non-coding RNAs, like HOXA-AS3, have been reported to regulate chemoresistance in several types of cancer. In this study, we aimed to determine whether HOXA-AS3 can mediate cisplatin resistance in bladder cancer, and its potential mechanism of action. We determined the viability, proliferation, and apoptosis of bladder cancer cells using a CCK-8 assay, EdU staining, and flow cytometry, respectively. We used western blot analysis to assess the expression of markers of epithelial-mesenchymal transition (EMT) and Notch1. We then confirmed expression of these EMT-related markers by immunofluorescence analysis. We found that hypoxia promoted resistance to cisplatin and upregulated the level of HOXA-AS3 in BC cells. Inhibition of HOXA-AS3 enhanced hypoxia-induced cisplatin sensitivity by regulating EMT and Notch1 in BC cells. A dual-luciferase reporter assay confirmed that HOXA-AS3 directly targets miR-455-5p and that Notch1 was a potential target of miRNA-455-5p. We also found that the positive effect of HOXA-AS3 inhibition on cisplatin resistance and tumorigenesis was alleviated when BC cells were transfected with miR-455-5p. Finally, we showed combining HOXA-AS3 small interfering RNA (siRNA) with cisplatin treatment inhibited tumorigenesis in a BALB/c nu/nu mouse model. Our findings indicate that HOXA-AS3 may function as a competing endogenous RNA (ceRNA) of miR-455-5p to regulate Notch1 and play an important role in regulating chemotherapeutic drug sensitivity in BC cells. Therefore, HOXA-AS3 may be a novel therapeutic target for treating bladder cancer.
History
References
- https://doi.org//10.1016/j.eururo.2016.06.010
- https://doi.org//10.3322/caac.21332
- https://doi.org//10.1016/j.ijpharm.2015.02.027
- https://doi.org//10.1016/j.ejphar.2014.07.025
- https://doi.org//10.3892/ijmm.2018.3374
- https://doi.org//10.1245/s10434-007-9705-0
- https://doi.org//10.1002/ijc.26475
- https://doi.org//10.1038/nature12986
- https://doi.org//10.1016/j.tcb.2017.11.008
- https://doi.org//10.1038/nrm3679
- https://doi.org//10.1007/978-1-4939-3378-5_21
- https://doi.org//10.4149/neo_2018_181218N980
- https://doi.org//10.1038/nature09144
- https://doi.org//10.1016/j.cell.2011.07.014
- https://doi.org//10.18632/aging.102307
- https://doi.org//10.2147/OTT.S197454
- https://doi.org//10.1242/dev.001065
- https://doi.org//10.1615/CritRevOncog.v16.i1-2.70
- https://doi.org//10.18632/oncotarget.12461
- https://doi.org//10.1093/abbs/gmz112
- https://doi.org//10.18632/oncotarget.18162
- https://doi.org//10.1038/s41419-018-0725-4
- https://doi.org//10.1093/abbs/gmz069
- https://doi.org//10.3892/etm.2019.7629
- https://doi.org//10.1159/000456066
- https://doi.org//10.1042/BSR20192457
- https://doi.org//10.1007/978-3-030-12734-3_9
- https://doi.org//10.1126/science.aaf4405
- https://doi.org//10.1016/j.tips.2012.01.005
- https://doi.org//10.1007/s13277-014-2056-0
- https://doi.org//10.1038/s41389-019-0170-y
- https://doi.org//10.1155/2015/865816
- https://doi.org//10.1089/cbr.2018.2503
- https://doi.org//10.1089/humc.2018.266
- https://doi.org//10.3390/molecules21070965
- https://doi.org//10.1159/000475910
- https://doi.org//10.2147/OTT.S201732
- https://doi.org//10.1007/s13277-014-2766-3
- https://doi.org//10.1016/j.gene.2016.07.034
- https://doi.org//10.18632/oncotarget.22565
- https://doi.org//10.1159/000367802
- https://doi.org//10.1038/nature16064
- https://doi.org//10.1007/s10620-019-05911-0
- https://doi.org//10.1089/gtmb.2018.0026