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CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to ot...

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Autores principales: Liu, Bin, Diaz Arguello, Olivia Adaly, Chen, Deng, Chen, Siwei, Saber, Ali, Haisma, Hidde J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228069/
https://www.ncbi.nlm.nih.gov/pubmed/32413049
http://dx.doi.org/10.1371/journal.pone.0232985
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author Liu, Bin
Diaz Arguello, Olivia Adaly
Chen, Deng
Chen, Siwei
Saber, Ali
Haisma, Hidde J.
author_facet Liu, Bin
Diaz Arguello, Olivia Adaly
Chen, Deng
Chen, Siwei
Saber, Ali
Haisma, Hidde J.
author_sort Liu, Bin
collection PubMed
description Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR(-/-) cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.
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spelling pubmed-72280692020-06-01 CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation Liu, Bin Diaz Arguello, Olivia Adaly Chen, Deng Chen, Siwei Saber, Ali Haisma, Hidde J. PLoS One Research Article Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR(-/-) cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma. Public Library of Science 2020-05-15 /pmc/articles/PMC7228069/ /pubmed/32413049 http://dx.doi.org/10.1371/journal.pone.0232985 Text en © 2020 Liu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liu, Bin
Diaz Arguello, Olivia Adaly
Chen, Deng
Chen, Siwei
Saber, Ali
Haisma, Hidde J.
CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
title CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
title_full CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
title_fullStr CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
title_full_unstemmed CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
title_short CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
title_sort crispr-mediated ablation of overexpressed egfr in combination with sunitinib significantly suppresses renal cell carcinoma proliferation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228069/
https://www.ncbi.nlm.nih.gov/pubmed/32413049
http://dx.doi.org/10.1371/journal.pone.0232985
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