1. Feedback activation of GATA1/miR-885-5p/PLIN3 pathway decreases sunitinib sensitivity in clear cell renal cell carcinoma.
- Author
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Yao D, Xia S, Jin C, Zhao W, Lan W, Liu Z, and Xiu Y
- Subjects
- Animals, Base Sequence, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Cell Line, Tumor, Down-Regulation drug effects, Down-Regulation genetics, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Kidney Neoplasms pathology, Lipid Droplets metabolism, Male, Mice, Inbred BALB C, Mice, Nude, MicroRNAs genetics, Middle Aged, Promoter Regions, Genetic genetics, Signal Transduction drug effects, Up-Regulation drug effects, Up-Regulation genetics, Carcinoma, Renal Cell drug therapy, Feedback, Physiological, GATA1 Transcription Factor metabolism, Kidney Neoplasms drug therapy, MicroRNAs metabolism, Perilipin-3 metabolism, Sunitinib therapeutic use
- Abstract
Sunitinib is the most commonly used first-line therapy for the treatment of advanced renal cell carcinoma (RCC), but intrinsic and extrinsic resistance to targeted therapies dramatically compromise the benefit of clinical outcome. Dissecting the underlying mechanisms and discovering reliable predictive biomarkers are urgently needed in clinic. Here, we discovered miR-885-5p was notably decreased after sunitinib treatment and associated with poor disease progression in clear cell renal cell carcinoma (ccRCC). In vitro and in vivo studies identified miR-885-5p inhibition contributed to sunitinib resistance. Mechanistically, sunitinib treatment reduced GATA1 expression, which in turn reduced its binding to MIR885 promoter and resulted in miR-885-5p downregulation in transcriptional level. In addition, PLIN3 was confirmed to be directly targeted by miR-885-5p and its upregulation significantly increased lipid droplets formation to decrease sunitinib sensitivity. Therefore, GATA1/miR-885-5p/ PLIN3 pathway may serve as a potential therapeutic strategy and a biomarker for sunitinib treatment in ccRCC.
- Published
- 2020
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