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EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy

Rationale: The oncogenesis of head and neck squamous cell carcinoma (HNSCC) is believed to result from oncogene activation and tumor suppressor inactivation. Here, we identified a new oncogenic role for the EREG gene in HNSCC. Methods: The TCGA database and immunohistochemistry assay were used to an...

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Autores principales: Liu, Shuli, Wang, Yang, Han, Yong, Xia, Weiya, Zhang, Ling, Xu, Shengming, Ju, Houyu, Zhang, Xiangkai, Ren, Guoxin, Liu, Liu, Ye, Weimin, Zhang, Zhiyuan, Hu, Jingzhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482801/
https://www.ncbi.nlm.nih.gov/pubmed/32929368
http://dx.doi.org/10.7150/thno.47176
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author Liu, Shuli
Wang, Yang
Han, Yong
Xia, Weiya
Zhang, Ling
Xu, Shengming
Ju, Houyu
Zhang, Xiangkai
Ren, Guoxin
Liu, Liu
Ye, Weimin
Zhang, Zhiyuan
Hu, Jingzhou
author_facet Liu, Shuli
Wang, Yang
Han, Yong
Xia, Weiya
Zhang, Ling
Xu, Shengming
Ju, Houyu
Zhang, Xiangkai
Ren, Guoxin
Liu, Liu
Ye, Weimin
Zhang, Zhiyuan
Hu, Jingzhou
author_sort Liu, Shuli
collection PubMed
description Rationale: The oncogenesis of head and neck squamous cell carcinoma (HNSCC) is believed to result from oncogene activation and tumor suppressor inactivation. Here, we identified a new oncogenic role for the EREG gene in HNSCC. Methods: The TCGA database and immunohistochemistry assay were used to analyze expression of EREG in HNSCC tissues. Immunoblotting was performed to identify the EGFR-mediated pathways altered by EREG. The role of EREG in oncogenesis was investigated in vivo and in vitro. Results: Upregulated EREG expression predicted a poor prognosis and triggered HNSCC oncogenic transformation by activating the epidermal growth factor receptor (EGFR) signaling pathway. We also demonstrated the direct association of EREG with EGFR and that this binding required EGFR domains I and III and the N57 residue of EREG. Moreover, EREG overexpression was shown to promote HNSCC oncogenesis by inducing C-Myc expression, and the pharmacological inhibition of C-Myc rescued EREG-promoted HNSCC oncogenesis. Unlike other EGFR ligands, EREG could mimic EGFR mutations by sustaining the activation of the EGFR-Erk pathway, and high EREG expression was positively associated with the response to treatment with the EGFR inhibitor erlotinib. Furthermore, knockdown of EREG decreased sensitivity to erlotinib treatment in vitro and in vivo. Conclusions: These results identify the EREG-EGFR-C-Myc pathway as a crucial axis that drives HNSCC oncogenesis and show that EREG expression could be a predictive functional marker of sensitivity to erlotinib therapy in HNSCC.
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spelling pubmed-74828012020-09-13 EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy Liu, Shuli Wang, Yang Han, Yong Xia, Weiya Zhang, Ling Xu, Shengming Ju, Houyu Zhang, Xiangkai Ren, Guoxin Liu, Liu Ye, Weimin Zhang, Zhiyuan Hu, Jingzhou Theranostics Research Paper Rationale: The oncogenesis of head and neck squamous cell carcinoma (HNSCC) is believed to result from oncogene activation and tumor suppressor inactivation. Here, we identified a new oncogenic role for the EREG gene in HNSCC. Methods: The TCGA database and immunohistochemistry assay were used to analyze expression of EREG in HNSCC tissues. Immunoblotting was performed to identify the EGFR-mediated pathways altered by EREG. The role of EREG in oncogenesis was investigated in vivo and in vitro. Results: Upregulated EREG expression predicted a poor prognosis and triggered HNSCC oncogenic transformation by activating the epidermal growth factor receptor (EGFR) signaling pathway. We also demonstrated the direct association of EREG with EGFR and that this binding required EGFR domains I and III and the N57 residue of EREG. Moreover, EREG overexpression was shown to promote HNSCC oncogenesis by inducing C-Myc expression, and the pharmacological inhibition of C-Myc rescued EREG-promoted HNSCC oncogenesis. Unlike other EGFR ligands, EREG could mimic EGFR mutations by sustaining the activation of the EGFR-Erk pathway, and high EREG expression was positively associated with the response to treatment with the EGFR inhibitor erlotinib. Furthermore, knockdown of EREG decreased sensitivity to erlotinib treatment in vitro and in vivo. Conclusions: These results identify the EREG-EGFR-C-Myc pathway as a crucial axis that drives HNSCC oncogenesis and show that EREG expression could be a predictive functional marker of sensitivity to erlotinib therapy in HNSCC. Ivyspring International Publisher 2020-08-25 /pmc/articles/PMC7482801/ /pubmed/32929368 http://dx.doi.org/10.7150/thno.47176 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Liu, Shuli
Wang, Yang
Han, Yong
Xia, Weiya
Zhang, Ling
Xu, Shengming
Ju, Houyu
Zhang, Xiangkai
Ren, Guoxin
Liu, Liu
Ye, Weimin
Zhang, Zhiyuan
Hu, Jingzhou
EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
title EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
title_full EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
title_fullStr EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
title_full_unstemmed EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
title_short EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
title_sort ereg-driven oncogenesis of head and neck squamous cell carcinoma exhibits higher sensitivity to erlotinib therapy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482801/
https://www.ncbi.nlm.nih.gov/pubmed/32929368
http://dx.doi.org/10.7150/thno.47176
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