1. BMP8A promotes survival and drug resistance via Nrf2/TRIM24 signaling pathway in clear cell renal cell carcinoma.
- Author
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Yu YP, Cai LC, Wang XY, Cheng SY, Zhang DM, Jian WG, Wang TD, Yang JK, Yang KB, and Zhang C
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Arsenic Trioxide pharmacology, Bone Morphogenetic Proteins genetics, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell metabolism, Carrier Proteins genetics, Cell Line, Tumor, Cell Proliferation, Cell Survival, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Male, Mice, Mice, Nude, NF-E2-Related Factor 2 genetics, Prognosis, Reactive Oxygen Species metabolism, Wnt Signaling Pathway, Bone Morphogenetic Proteins metabolism, Carcinoma, Renal Cell pathology, Carrier Proteins metabolism, Drug Resistance, Neoplasm drug effects, Kidney Neoplasms pathology, NF-E2-Related Factor 2 metabolism
- Abstract
There is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK-8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As
2 O3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1-mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP-qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As2 O3 . Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2020
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