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.
Keywords:
RCC; miR-885-5p; sunitinib.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Base Sequence
-
Carcinoma, Renal Cell / drug therapy*
-
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
-
Feedback, Physiological*
-
Female
-
GATA1 Transcription Factor / metabolism*
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Kidney Neoplasms / drug therapy*
-
Kidney Neoplasms / pathology
-
Lipid Droplets / metabolism
-
Male
-
Mice, Inbred BALB C
-
Mice, Nude
-
MicroRNAs / genetics
-
MicroRNAs / metabolism*
-
Middle Aged
-
Perilipin-3 / metabolism*
-
Promoter Regions, Genetic / genetics
-
Signal Transduction / drug effects
-
Sunitinib / therapeutic use*
-
Up-Regulation / drug effects
-
Up-Regulation / genetics
Substances
-
GATA1 Transcription Factor
-
MIRN885 microRNA, human
-
MicroRNAs
-
PLIN3 protein, human
-
Perilipin-3
-
Sunitinib
Grants and funding
The work was supported by grants from the Key Project of Heilongjiang Natural Science Foundation [ZD201516], the 60th China Post-Doctoral Science Foundation [2016M601450] and the Overseas Scholars Project of Heilongjiang Education Department [QC2014C112].