DIA-MS Identifies and Validates Transgelin as Protein
Contributing to a Poor Response of Metastatic Renal Cell
Carcinoma to Sunitinib Treatment

a 2021

DIA-MS Identifies and Validates Transgelin as Protein Contributing to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment

BOUCHALOVÁ, Pavla, Jindřich BERÁNEK, Petr LAPČÍK, David POTĚŠIL, Ján PODHOREC et. al.

Základní údaje

Originální název

DIA-MS Identifies and Validates Transgelin as Protein Contributing to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment

Název česky

DIA-MS analýza identifikovala a validovala transgelin jako protein přispívající ke slabé odpovědi na léčbu sunitinibem u metastatického karcinomu ledvin

Autoři

BOUCHALOVÁ, Pavla, Jindřich BERÁNEK, Petr LAPČÍK, David POTĚŠIL, Ján PODHOREC, Milan HORA, Ondřej FIALA, Alexandr POPRACH a Pavel BOUCHAL

Vydání

HUPO Reconnect 2021, 2021

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

renal carcinoma, sunitinib, resistance, DIA proteomics, transgelin, silencing technique, proliferation, survival

Příznaky

Mezinárodní význam

Změněno: 28. 1. 2022 12:39, doc. Mgr. Pavel Bouchal, Ph.D.

Anotace

V originále

Introduction. 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 (mccRCC) with good or intermediate prognosis. However, about one-third of mccRCC patients do not respond to sunitinib, leading to disease progression. Methods. Here, we aim to find and characterize proteins associated with poor sunitinib response. 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 (DIA-MS) on Impact II LC-MS system (Bruker), together with their adjacent non-cancerous tissues in a pilot proteomics study. Validation was performed in an independent cohort of 75 mccRCC patients using DIA-MS on QExactive HF-X (Thermo Fisher Scientific), with data analysis in Spectronaut 13.9 (Biognosys). Transgelin protein role was functionally analyzed in RCC cell lines using CRISPR and RNAi silencing techniques. Results. Proteomics analysis quantified 1996 protein groups (FDR=0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib in the pilot study, representing a pattern of proteins potentially contributing to sunitinib resistance. Validation cohort confirmed up-regulation of transgelin in tumors non-responding to sunitinib and revealed its association with tumor grade. Gene set enrichment analysis showed an up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant proteins. Reduced transgelin protein level in CRISPR and RNAi altered RCC cells led to significantly slower proliferation of these cells and affected their survival. Conclusion. Altogether, our data indicate that transgelin is an essential protein supporting RCC cell proliferation, which could contribute to intrinsic sunitinib resistance, and is associated with aggressive phenotype of RCC tumors.

Návaznosti

MUNI/A/1604/2020, interní kód MU

Název: Podpora biochemického výzkumu v roce 2021

Investor: Masarykova univerzita, Podpora biochemického výzkumu v roce 2021

NV19-08-00250, projekt VaV

Název: Proteotypová klasifikace renálního karcinomu ve vztahu k prognóze a terapeutické odpovědi

Investor: Ministerstvo zdravotnictví ČR, Proteotypová klasifikace renálního karcinomu ve vztahu k prognóze a terapeutické odpovědi

Citovat

BOUCHALOVÁ, Pavla, Jindřich BERÁNEK, Petr LAPČÍK, David POTĚŠIL, Ján PODHOREC, Milan HORA, Ondřej FIALA, Alexandr POPRACH a Pavel BOUCHAL. DIA-MS Identifies and Validates Transgelin as Protein Contributing to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment. In HUPO Reconnect 2021. 2021.

@proceedings{1804898,
   author = {Bouchalová, Pavla and Beránek, Jindřich and Lapčík, Petr and Potěšil, David and Podhorec, Ján and Hora, Milan and Fiala, Ondřej and Poprach, Alexandr and Bouchal, Pavel},
   booktitle = {HUPO Reconnect 2021},
   keywords = {renal carcinoma, sunitinib, resistance, DIA proteomics, transgelin, silencing technique, proliferation, survival},
   language = {eng},
   title = {DIA-MS Identifies and Validates Transgelin as Protein Contributing to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment},
   url = {https://hupo2021.org/wp-content/uploads/2021/11/HUPO-2021-Abstract-Book_Oct-27.pdf},
   year = {2021}
}

TY  - CONF
ID  - 1804898
AU  - Bouchalová, Pavla - Beránek, Jindřich - Lapčík, Petr - Potěšil, David - Podhorec, Ján - Hora, Milan - Fiala, Ondřej - Poprach, Alexandr - Bouchal, Pavel
PY  - 2021
TI  - DIA-MS Identifies and Validates Transgelin as Protein Contributing to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment
KW  - renal carcinoma, sunitinib, resistance, DIA proteomics, transgelin, silencing technique, proliferation, survival
UR  - https://hupo2021.org/wp-content/uploads/2021/11/HUPO-2021-Abstract-Book_Oct-27.pdf
N2  - Introduction. 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 (mccRCC) with good or intermediate prognosis. However, about one-third of mccRCC patients do not respond to sunitinib, leading to disease progression. Methods. Here, we aim to find and characterize proteins associated with poor sunitinib response. 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 (DIA-MS) on Impact II LC-MS system (Bruker), together with their adjacent non-cancerous tissues in a pilot proteomics study. Validation was performed in an independent cohort of 75 mccRCC patients using DIA-MS on QExactive HF-X (Thermo Fisher Scientific), with data analysis in Spectronaut 13.9 (Biognosys). Transgelin protein role was functionally analyzed in RCC cell lines using CRISPR and RNAi silencing techniques. Results. Proteomics analysis quantified 1996 protein groups (FDR=0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib in the pilot study, representing a pattern of proteins potentially contributing to sunitinib resistance. Validation cohort confirmed up-regulation of transgelin in tumors non-responding to sunitinib and revealed its association with tumor grade. Gene set enrichment analysis showed an up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant proteins. Reduced transgelin protein level in CRISPR and RNAi altered RCC cells led to significantly slower proliferation of these cells and affected their survival. Conclusion. Altogether, our data indicate that transgelin is an essential protein supporting RCC cell proliferation, which could contribute to intrinsic sunitinib resistance, and is associated with aggressive phenotype of RCC tumors.
ER  -

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