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

Frontiers in Oncology

Yan-Qiu Zhao¹  Wei-Tao Liu²  Ying-Chen Qian²  Chao-Shan Wang²  Yi-Fan Lu²  Min Wang²  Bing-Hua Jiang³  Lin Wang⁴  Yun-Xia Xie⁴ 

[1] Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China;Department of Pathology, Nanjing Medical University, Nanjing, China;Department of Pathology, The University of Iowa, Iowa City, IA, United States;The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China;

关键词: HB-EGF;    arsenic;    lung cancer;    PKM2;    HIF-1α;   

DOI  :  10.3389/fonc.2020.01019

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown