Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway  

作　　者：Yilin ZHU Fanrong LIU Lei LIU Jinfu WANG Fengyuan GAO Lan YE Honglei WU Chengjun ZHOU Guimei LIN Xiaogang ZHAO Peichao LI 

机构地区：[1]Department of Thoracic Surgery,The Second Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [2]Cancer Center,The Second Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [3]Department of Gastroenterology,The Second Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [4]Department of Pathology,The Second Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [5]Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [6]National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products,Shandong University,Jinan 250012,China [7]Key Laboratory of Chest Cancer,The Second Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250012,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2025年第1期76-91,共16页浙江大学学报(英文版)B辑(生物医学与生物技术)

基　　金：supported by the Special Construction Project Fund for Taishan Mountain Scholars of Shandong Province;the Jinan Medicine Research Program;the Nurturing and Development Fund from The Second Hospital of Shandong University(No.2022YP62);the Shandong Provincial Natural Science Foundation for Young Scholars(No.ZR2022QH285),China.

摘　　要：Hexavalent chromium Cr(Ⅵ),as a well-established carcinogen,contributes to tumorigenesis for many human cancers,especially respiratory and digestive tumors.However,the potential function and relevant mechanism of Cr(Ⅵ)on the initiation of esophageal carcinogenesis are largely unknown.Here,immortalized human esophageal epithelial cells(HEECs)were induced to be malignantly transformed cells,termed HEEC-Cr(Ⅵ)cells,via chronic exposure to Cr(Ⅵ),which simulates the progress of esophageal tumorigenesis.In vitro and in vivo experiments demonstrated that HEEC-Cr(Ⅵ)cells obtain the ability of anchorage-independent growth,greater proliferative capacity,cancer stem cell properties,and the capacity to form subcutaneous xenografts in BALB/c nude mice when compared to their parental cells,HEECs.Additionally,HEEC-Cr(Ⅵ)cells exhibited weakened cell motility and enhanced cell adhesion.Interestingly,HEECs with acute exposure to Cr(Ⅵ)failed to display those malignant phenotypes of HEEC-Cr(Ⅵ)cells,suggesting that Cr(Ⅵ)-induced malignant transformation,but not Cr(Ⅵ)itself,is the cause for the tumor characteristics of HEEC-Cr(Ⅵ)cells.Mechanistically,chronic exposure to Cr(Ⅵ)induced abnormal activation of Notch signaling,which is crucial to maintaining the capacity for malignant proliferation and stemness of HEEC-Cr(Ⅵ)cells.As expected,N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester(DAPT),an inhibitor for the Notch pathway,drastically attenuated cancerous phenotypes of HEEC-Cr(Ⅵ)cells.In conclusion,our study clarified the molecular mechanism underlying Cr(Ⅵ)-induced esophageal tumorigenesis,which provides novel insights for further basic research and clinical therapeutic strategies about Cr(Ⅵ)-associated esophageal cancer.

关 键 词：Hexavalent chromium Cr(Ⅵ) Esophageal tumorigenesis Malignant proliferation STEMNESS Notch signaling pathway 

分 类 号：R73[医药卫生—肿瘤]