Abstract
Upon sunitinib treatment of metastatic renal cell carcinoma patients eventually acquire resistance. Our aim was to investigate microRNAs behind sunitinib resistance.We developed an in vivo xenograft and an in vitro model and compared morphological, immunhistochemical, transcriptomical and miRNome data changes during sunitinib response and resistance by performing next-generation mRNA and miRNA sequencing. Complex bioinformatics (pathway, BioFunction and network) analysis were performed. Results were validated by in vitro functional assays.Our morphological, immunhistochemical, transcriptomical and miRNome data all pointed out that during sunitinib resistance tumor cells changed to migratory phenotype. We identified the downregulated miR-1 and miR-663a targeting FRAS1 (Fraser Extracellular Matrix Complex Subunit 1) and MDGA1 (MAM Domain Containing Glycosylphosphatidylinositol Anchor 1) in resistant tumors. We proved firstly miR-1-FRAS1 and miR-663a-MDGA1 interactions. We found that MDGA1 knockdown decreased renal cancer cell migration and proliferation similarly to restoration of levels of miR-1 and miR-663.Our results support the central role of cell migration as an adaptive mechanism to secure tumor survival behind sunitinib resistance. MDGA1, FRAS1 or the targeting miRNAs can be potential adjuvant therapeutic targets, through inhibition of cancer cell migration, thus eliminating the development of resistance and metastasis.
Highlights
Renal cell carcinoma (RCC) is the most frequent malignancy of the adult kidney and its incidence has been steadily rising by 2–4% each year [1]
Characterization of sunitinib sensitive and resistant xenograft RCC tumors Mice were subcutaneously injected with human renal cell carcinoma cell lines
Sunitinib resistance is a significant problem in treatment of metastatic RCC
Summary
Renal cell carcinoma (RCC) is the most frequent malignancy of the adult kidney and its incidence has been steadily rising by 2–4% each year [1]. The angiogenesis-inhibitor sunitinib is the first-line therapy for metastatic RCC This small molecule multi-tyrosine kinase inhibitor [4] inhibits VEGFR-1, -2, -3, PDGFR-α and PDGFR-β, Fms-like tyrosine kinase 3 (FLT3), stem cell factor receptor (KIT), colony stimulating factor receptor type 1 receptor; and the glial cell line–derived neurotrophic factor receptor [8, 9]. Sunitinib treatment prolonged both progression-free and overall survival [10] and response rates to sunitinib were higher compared to interferon [11, 12]
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