Elucidating mechanisms of sunitinib resistance in renal cancer: an integrated pathological-molecular analysis

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.

An endothelial microRNA-1–regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis

“…29 miR-1 regulates a range of molecular mechanisms in myoblasts and cardiomyocytes [86][87][88] and modulates tumor progression and angiogenesis. 32,[89][90][91][92] Our present findings assign a completely novel function to endothelial miR-1.…”

Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer

“…For example, a FRAS1‐knockdown in a lung cancer cell line inactivates the FAK pathway and suppresses tumor invasion and migration . FRAS1 is involved with resistance of ovarian cancer to carboplatin and the resistance of renal cancer to sunitinib . Furthermore, analysis of a xenograft model of human endometrial cancer concluded that FRAS1 is a promising diagnostic marker .…”

“…22 FRAS1 is involved with resistance of ovarian cancer to carboplatin 23 and the resistance of renal cancer to sunitinib. 24 Furthermore, analysis of a xenograft model of human endometrial cancer concluded that FRAS1 is a promising diagnostic marker. 25 To the best of our knowledge, the association of FRAS1 with gastroenterological cancer remains unclear.…”

Characterisation of the Morphological, Functional and Molecular Changes in Sunitinib-Resistant Renal Cell Carcinoma Cells

“…Despite larger nucleus or nuclear atypia, the surprising finding was the lack of functional aspects in resistant cells that are often considered as “aggressive” in cancer biology, as they did not show any significant difference when compared with the parental cells. For example, Burtz et al ( 42 ), in an in vivo experimental model, reported that sunitinib-resistant renal tumours exhibited aggressive behaviour such as sarcomatoid differentiation, extensive vascular and local invasion, and liver and lung metastases. In our study, resistant cells did not show any significant changes in growth or transmigration when compared with parental cells.…”