Abstract
A multiple receptor tyrosine kinase inhibitor, sunitinib, is a first-line therapy for clear cell renal cell carcinoma (CCRCC). Unfortunately, it has the major challenges of low initial response rate and resistance after about one year of treatment. Here we evaluated a microRNA (miRNA) and its target responsible for sunitinib resistance. Using miRNA profiling, we identified miR-96-5p upregulation in tumors from sunitinib-resistant CCRCC patients. By bioinformatic analysis, PTEN was selected as a potential target of miR-96-5p, which showed low levels in tumors from sunitinib-resistant CCRCC patients. Furthermore, PTEN and miR-96-5p levels were negatively correlated in a large The Cancer Genome Atlas kidney renal clear cell carcinoma cohort and high miR-96 and low PTEN represented poor prognosis in this cohort. Additionally, four-week sunitinib treatment increased miR-96-5p and decreased PTEN only in tumors from a sunitinib-resistant patient-derived xenograft model. We found a novel miR-96-5p binding site in the PTEN 3′ UTR and confirmed direct repression by luciferase reporter assay. Furthermore, we demonstrated that repression of PTEN by miR-96-5p increased cell proliferation and migration in sunitinib-treated cell lines. These results highlight the direct suppression of PTEN by miR-96-5p and that high miR-96-5p and low PTEN are partially responsible for sunitinib resistance and poor prognosis in CCRCC.
Highlights
Worldwide, approximately 338,000 new cases of renal cell carcinoma (RCC) are diagnosed and 175,000 patients die from RCC each y ear[1]
Using miRNA profiling, we found that miR-96-5p was significantly increased in sunitinibresistant tumors compared with the level in sensitive tumors from clear cell renal cell carcinoma (CCRCC) patients and confirmed its expression in tumors from a CCRCC patient-derived xenograft (PDX) model
Consistent with this, the level of PTEN was inversely associated with miR-96 in 514 patients of the kidney renal clear cell carcinoma (KIRC) cohort in The Cancer Genome Atlas (TCGA) data and a resistant PDX model
Summary
Approximately 338,000 new cases of renal cell carcinoma (RCC) are diagnosed and 175,000 patients die from RCC each y ear[1]. VHL loss is associated with the accumulation of hypoxia-inducible factor 1 (HIF-1) and increased transcription of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), leading to intense vascularity[2] For this reason, therapeutic agents targeting VEGF receptor (VEGFR) signaling have been shown to improve disease control. Treatment with sunitinib showed slightly longer overall survival (OS) than cytokine therapies, the initial response rate is 30%–40% and disease progression occurred in sensitive patients who survived 6–15 months after sunitinib t reatment[2] This indicates that there is de novo and acquired resistance against sunitinib in CCRCC. Male Female Mean std Mean std Mean std Mean std Death Survival Mean std miRNAs in tumor tissues and liquid biopsies from cancer patients may be effective for accurately determining the diagnosis, prognosis, and drug s ensitivity[4] In accordance with this trend, substantial information on CCRCC has been accumulated. These results suggest that miR-96-5p mediates sunitinib resistance in CCRCC in a PTEN-dependent manner
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