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HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and dev...

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Autores principales: Wang, Lin, Lu, Yi-Fan, Wang, Chao-Shan, Xie, Yun-Xia, Zhao, Yan-Qiu, Qian, Ying-Chen, Liu, Wei-Tao, Wang, Min, Jiang, Bing-Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338480/
https://www.ncbi.nlm.nih.gov/pubmed/32695675
http://dx.doi.org/10.3389/fonc.2020.01019
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author Wang, Lin
Lu, Yi-Fan
Wang, Chao-Shan
Xie, Yun-Xia
Zhao, Yan-Qiu
Qian, Ying-Chen
Liu, Wei-Tao
Wang, Min
Jiang, Bing-Hua
author_facet Wang, Lin
Lu, Yi-Fan
Wang, Chao-Shan
Xie, Yun-Xia
Zhao, Yan-Qiu
Qian, Ying-Chen
Liu, Wei-Tao
Wang, Min
Jiang, Bing-Hua
author_sort Wang, Lin
collection PubMed
description Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway.
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spelling pubmed-73384802020-07-20 HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth Wang, Lin Lu, Yi-Fan Wang, Chao-Shan Xie, Yun-Xia Zhao, Yan-Qiu Qian, Ying-Chen Liu, Wei-Tao Wang, Min Jiang, Bing-Hua Front Oncol Oncology Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway. Frontiers Media S.A. 2020-06-30 /pmc/articles/PMC7338480/ /pubmed/32695675 http://dx.doi.org/10.3389/fonc.2020.01019 Text en Copyright © 2020 Wang, Lu, Wang, Xie, Zhao, Qian, Liu, Wang and Jiang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Wang, Lin
Lu, Yi-Fan
Wang, Chao-Shan
Xie, Yun-Xia
Zhao, Yan-Qiu
Qian, Ying-Chen
Liu, Wei-Tao
Wang, Min
Jiang, Bing-Hua
HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth
title HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth
title_full HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth
title_fullStr HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth
title_full_unstemmed HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth
title_short HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth
title_sort hb-egf activates the egfr/hif-1α pathway to induce proliferation of arsenic-transformed cells and tumor growth
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338480/
https://www.ncbi.nlm.nih.gov/pubmed/32695675
http://dx.doi.org/10.3389/fonc.2020.01019
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