Transgelin contributes to a poor response of metastatic renal cell carcinoma to sunitinib treatment
| Authors | |
|---|---|
| Year of publication | 2020 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Introduction. Renal cell carcinoma (RCC) represents about 2-3% of all cancers with over 400,000 new cases per year with an increasing incidence worldwide. Sunitinib, a vascular endothelial growth factor (VEGF) tyrosin kinase receptor inhibitor, has been used for first-line treatment of metastatic RCC (mRCC) with good or intermediate prognosis. About one third of mRCC patients, however, do not respond well to sunitinib. The aim of presented pilot study was to find proteins associated with poor sunitinib response. Methods. 8 vs. 8 RCC tumors from patients responding vs. non-responding to sunitinib in 3 months after treatment initiation, and their adjacent normal tissues, were analyzed using LC-MS proteomics in data independent acquisition (DIA) mode on Impact II LC-MS system (Bruker). The most promising proteins were functionally analyzed via CRISPR/Cas9 technology in 786-0 RCC cell line and using proliferation tests. Results. Proteomics analysis quantified 2012 protein groups (FDR<0.01) and revealed 42 proteins deregulated in primary tumors non-responding vs. responding to sunitinib. Gene set enrichment analysis showed enriched elastic fibres, vesicular transport and transport of small molecules pathways. Based on the above, transgelin, a well-known structural protein involved in actin remodeling, was selected for functional analysis. TAGLN gene was successfully disrupted by CRISPR/Cas9. The cells with reduced level of transgelin then exhibited significantly slower proliferation. Conclusion. DIA proteomics analysis revealed a pattern of de-regulated proteins possibly directly or indirectly contributing to sunitinib resistance. The data shows that transgelin supports survival of RCC cells and could contribute to their intrinsic sunitinib resistance. |
| Related projects: |