Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Proteomics
2.2.1. Lysis of Tissue Samples
2.2.2. Preparing Samples for Mass Spectrometry (MS) Analysis
2.2.3. Peptide Desalting Prior to LC-MS/MS
2.2.4. Liquid Chromatography (LC)-MS Analysis of Peptides
2.2.5. MS Data Analysis
2.2.6. Functional Analysis of Identified Proteins
2.3. Cellular Studies
2.3.1. Cell Cultures and Cultivation
2.3.2. Immunoblotting
2.3.3. CRISPR/Cas9 Gene Editing
2.3.4. Monoclonal Selection of CRISPR Modified Cells and Their Cultivation
2.3.5. siRNA Transfection, Cultivation of siRNA-Transfected Cells, and Scratch Assay
2.4. Statistical Analysis
3. Results
3.1. Spectral Library and Mass Spectrometry Data Matrix
3.2. Proteins Associated with Sunitinib Non-Responders
3.3. Hallmark and BIOCARTA Pathways, Reactome, and GO Associated with Sunitinib Non-Responders
3.4. Proteins Differentially Abundant in mccRCC Tumors vs. Adjacent Non-Cancerous Tissue
3.5. Pathways Enriched in mccRCC Tumors Compared to Non-Cancerous Tissues
3.6. CRISPR/Cas9 Knock-Down Shows That Transgelin Is Essential for the Proliferation of 786-0 RCC Cells
3.7. Transient Silencing of Transgelin Slows the Proliferation of 786-0 Cells Down
4. Discussion
4.1. Transgelin Is the Key Identified Protein in Intrinsic Sunitinib Resistance through Proliferation Support and EMT
4.2. Other Relevant Proteins in Sunitinib Non-Responding Tumors
4.3. Role of Enriched Signaling Pathways in Sunitinib Resistance
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Categories/Groups | Patients (n = 16) | Responders (R, n = 8) | Non-Responders (NR, n = 8) | |
---|---|---|---|---|
sex | M | 10 | 5 | 5 |
F | 6 | 3 | 3 | |
age at diagnosis, mean (yrs) | 63.7 ± 9.5 | 69.0 ± 5.5 | 58.4 ± 10.3 | |
Fuhrman grade | 1 | 1 | 1 | 0 |
2 | 3 | 2 | 1 | |
3 | 8 | 4 | 4 | |
4 | 4 | 1 | 3 | |
pT | 1a | 1 | 1 | 0 |
1b | 3 | 3 | 0 | |
2a | 1 | 1 | 0 | |
2b | 1 | 0 | 1 | |
3a | 5 | 2 | 3 | |
3b | 1 | 0 | 1 | |
4 | 4 | 1 | 3 | |
pN | 0 | 12 | 7 | 5 |
1 | 2 | 0 | 2 | |
2 | 2 | 1 | 1 | |
mestastases at diagnosis | 0 | 4 | 4 | 0 |
1 | 12 | 4 | 8 | |
relapse after surgery | yes | 4 | 4 | 0 |
no | 12 | 4 | 8 | |
sunitinib response | CR | 1 | 1 | 0 |
PR | 7 | 7 | 0 | |
PD | 8 | 0 | 8 |
P vs. R | P vs. N | R vs. N | |||||||
---|---|---|---|---|---|---|---|---|---|
Genes | Protein | Uniprot ID | AVG Log2 Ratio | q Value | AVG Log2 Ratio | q Value | AVG Log2 Ratio | q Value | |
1 | LTF | Lactotransferrin | P02788 | 2.445 | 0.004 | 2.237 | 0.001 | −0.208 | 0.531 |
2 | TAGLN | Transgelin | Q01995 | 2.407 | 0.007 | 2.667 | 0.021 | 0.260 | 0.328 |
3 | CLU | Clusterin | P10909 | 2.235 | 0.029 | 2.781 | 0.041 | 0.546 | 0.242 |
4 | ORM2 | Alpha-1-acid glycoprotein 2 | P19652 | 1.623 | 0.020 | 2.850 | 0.008 | 1.227 | 0.516 |
5 | S100A9 | Protein S100-A9 | P06702 | 1.553 | 0.035 | 2.659 | 0.006 | 1.106 | 0.397 |
6 | CFH | Complement factor H | P08603 | 1.542 | 0.019 | 2.936 | 0.000 | 1.395 | 0.228 |
7 | SERPINA3 | Alpha-1-antichymotrypsin | P01011 | 1.491 | 0.002 | 2.906 | 0.000 | 1.415 | 0.162 |
8 | HPX | Hemopexin | P02790 | 1.400 | 0.000 | 2.616 | 0.000 | 1.216 | 0.055 |
9 | PLG | Plasminogen | P00747 | 1.345 | 0.001 | 3.213 | 0.000 | 1.868 | 0.201 |
10 | SERPINC1 | Antithrombin-III | P01008 | 1.309 | 0.024 | 1.831 | 0.015 | 0.521 | 0.517 |
11 | KNG1 | Kininogen-1 | P01042 | 1.180 | 0.007 | 2.403 | 0.000 | 1.223 | 0.111 |
12 | SERPINA1 | Alpha-1-antitrypsin | P01009 | 1.150 | 0.000 | 2.420 | 0.000 | 1.270 | 0.475 |
13 | MYH11 | Myosin-11 | P35749 | 1.133 | 0.000 | 2.197 | 0.000 | 1.064 | 0.130 |
14 | CP | Ceruloplasmin | P00450 | 1.108 | 0.003 | 2.660 | 0.000 | 1.553 | 0.060 |
15 | ITIH4 | Inter-alpha-trypsin inhibitor heavy chain H4 | Q14624 | 0.888 | 0.029 | 1.865 | 0.011 | 0.977 | 0.396 |
16 | IGHM | Immunoglobulin heavy constant mu | P01871 | 0.826 | 0.025 | 2.562 | 0.000 | 1.735 | 0.181 |
17 | CLTC | Clathrin heavy chain 1 | Q00610 | 0.784 | 0.001 | 1.075 | 0.007 | 0.291 | 0.373 |
18 | ERP29 | Endoplasmic reticulum resident protein 29 | P30040 | −0.610 | 0.039 | −1.019 | 0.004 | −0.409 | 0.209 |
19 | NDUFB11 | NADH-ubiquinone oxidoreductase ESSS subunit | Q9NX14 | −0.617 | 0.046 | −1.765 | 0.010 | −1.148 | 0.129 |
20 | HSD17B4 | Peroxisomal multifunctional enzyme type 2 | P51659 | −0.618 | 0.003 | −0.841 | 0.000 | −0.223 | 0.148 |
21 | DNPH1 | 2′-deoxynucleoside 5′-phosphate N-hydrolase 1 | O43598 | −0.785 | 0.036 | −0.751 | 0.025 | 0.034 | 0.355 |
22 | CTSC | Dipeptidyl peptidase 1 | P53634 | −0.804 | 0.019 | −0.969 | 0.001 | −0.165 | 0.406 |
23 | HSPA12A | Heat shock 70 kDa protein 12A | O43301 | −0.806 | 0.025 | −0.856 | 0.002 | −0.050 | 0.408 |
24 | DYNLL2 | Dynein light chain 2, cytoplasmic | Q96FJ2 | −0.858 | 0.039 | −1.066 | 0.001 | −0.208 | 0.222 |
25 | PPME1 | Protein phosphatase methylesterase 1 | Q9Y570 | −0.889 | 0.022 | −3.817 | 0.048 | −2.928 | 0.260 |
26 | ACSS1 | Acetyl-coenzyme A synthetase 2-like, mitochondrial | Q9NUB1 | −1.666 | 0.041 | −1.816 | 0.021 | −0.150 | 0.503 |
27 | GSTA2 | Glutathione S-transferase A2 | P09210 | −2.219 | 0.000 | −1.776 | 0.000 | 0.443 | 0.389 |
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Bouchalova, P.; Beranek, J.; Lapcik, P.; Potesil, D.; Podhorec, J.; Poprach, A.; Bouchal, P. Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment. Biomedicines 2021, 9, 1145. https://doi.org/10.3390/biomedicines9091145
Bouchalova P, Beranek J, Lapcik P, Potesil D, Podhorec J, Poprach A, Bouchal P. Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment. Biomedicines. 2021; 9(9):1145. https://doi.org/10.3390/biomedicines9091145
Chicago/Turabian StyleBouchalova, Pavla, Jindrich Beranek, Petr Lapcik, David Potesil, Jan Podhorec, Alexandr Poprach, and Pavel Bouchal. 2021. "Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment" Biomedicines 9, no. 9: 1145. https://doi.org/10.3390/biomedicines9091145