Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment

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Authors

BOUCHALOVÁ Pavla BERÁNEK Jindřich LAPČÍK Petr POTĚŠIL David PODHOREC Ján POPRACH Alexandr BOUCHAL Pavel

Year of publication 2021
Type Article in Periodical
Magazine / Source Biomedicines
MU Faculty or unit

Faculty of Science

Citation
Web https://www.mdpi.com/2227-9059/9/9/1145
Doi http://dx.doi.org/10.3390/biomedicines9091145
Keywords mccRCC; sunitinib; resistance; DIA-MS; transgelin
Description Renal cell carcinoma (RCC) represents about 2–3% of all cancers with over 400,000 new cases per year. Sunitinib, a vascular endothelial growth factor tyrosine kinase receptor inhibitor, has been used mainly for first-line treatment of metastatic clear-cell RCC with good or intermediate prognosis. However, about one-third of metastatic RCC patients do not respond to sunitinib, leading to disease progression. Here, we aim to find and characterize proteins associated with poor sunitinib response in a pilot proteomics study. Sixteen RCC tumors from patients responding (8) vs. non-responding (8) to sunitinib 3 months after treatment initiation were analyzed using data-independent acquisition mass spectrometry, together with their adjacent non-cancerous tissues. Proteomics analysis quantified 1996 protein groups (FDR = 0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib, representing a pattern of deregulated proteins potentially contributing to sunitinib resistance. Gene set enrichment analysis showed an up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant proteins. Transgelin expression was silenced by CRISPR/Cas9 and RNA interference, and the cells with reduced transgelin level exhibited significantly slower proliferation. Our data indicate that transgelin is an essential protein supporting RCC cell proliferation, which could contribute to intrinsic sunitinib resistance.
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