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

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

doi:10.1631/jzus.B2300896

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Research Article | Updated：2025-04-21

Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway
Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway
六价铬的慢性暴露可通过激活Notch信号通路诱导食管肿瘤发生
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 26, Issue 1, Pages: 76-91(2025)
Affiliations：

1.Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan250012, China
2.Cancer Center, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan250012, China
3.Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan250012, China
4.Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan250012, China
5.Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan250012, China
6.National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products, Shandong University, Jinan250012, China
7.Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan250012, China
Funds：
DOI：10.1631/jzus.B2300896
CLC：
CSTR：
Received：10 December 2023，

Revised：17 June 2024，

Published Online：21 October 2024，

Published：15 January 2025
Accepted：

朱一林,刘繁荣,刘雷等.六价铬的慢性暴露可通过激活Notch信号通路诱导食管肿瘤发生[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(01):76-91.

Yilin ZHU, Fanrong LIU, Lei LIU, et al. Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(1): 76-91.
朱一林,刘繁荣,刘雷等.六价铬的慢性暴露可通过激活Notch信号通路诱导食管肿瘤发生[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(01):76-91. DOI： 10.1631/jzus.B2300896.

Yilin ZHU, Fanrong LIU, Lei LIU, et al. Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(1): 76-91. DOI： 10.1631/jzus.B2300896.

摘要

六价铬Cr(VI)是一种公认的致癌物，对多种癌症尤其是呼吸道和消化道肿瘤的发生具有促进作用。然而，Cr(VI)在食管癌发生中的潜在作用和相关机制仍未知。本研究选取永生化的人食管上皮细胞（HEECs），通过长期Cr(VI)暴露获得恶性转化细胞系（HEEC-Cr(VI)），以模拟Cr(VI)诱导食管肿瘤发生进程。体外和体内实验表明，与亲代细胞HEECs相比，HEEC-Cr(VI)细胞获得了锚定非依赖性生长的特性、增强的增殖能力、癌症干细胞特性以及在BALB/c裸鼠皮下成瘤的能力。此外，HEEC-Cr(VI)细胞表现出减弱的细胞运动能力以及增强的细胞粘附性。但经过Cr(VI)急性暴露的HEECs细胞未能获得HEEC-Cr(VI)细胞的恶性表型，这表明HEEC-Cr(VI)细胞的恶性表型来源于Cr(VI)诱导的恶性转化，而不是由Cr(VI)直接导致。对其机制的探究结果揭示，长期Cr(VI)暴露诱导的Notch信号通路的异常激活对维持HEEC-Cr(VI)细胞的恶性增殖能力和干性至关重要，而Notch通路的抑制剂DAPT能显著削弱HEEC-Cr(VI)细胞的恶性表型。综上所述，本研究阐明了Cr(VI)诱导食管肿瘤发生的分子机制，为Cr(VI)相关食管癌的基础研究和临床治疗策略提供了新方向。

Abstract

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 t

ransformation

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

-‍[

-‍(3

5-difluorophenacetyl)‍-L-alanyl

]

‍-

-phenylglycine

-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

Keywords

references

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Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Disease, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province

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