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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2025 Vol.26 No.1 P.76-91
Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway
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 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-phenylglycinet-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.
Key words: Hexavalent chromium Cr(VI); Esophageal tumorigenesis; Malignant proliferation; Stemness; Notch signaling pathway
1山东大学第二医院胸外科， 中国济南市， 250012
2山东大学第二医院肿瘤防治中心， 中国济南市， 250012
3山东大学第二医院消化内科， 中国济南市， 250012
4山东大学第二医院病理科， 中国济南市， 250012
5天然产物化学生物学教育部重点实验室， 中国济南市， 250012
6国家药品监督管理局药物制剂技术研究与评价重点实验室， 中国济南市， 250012
7山东大学第二医院胸部肿瘤重点实验室， 中国济南市， 250012
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。
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DOI:
10.1631/jzus.B2300896
CLC number:
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On-line Access:
2025-01-14
Received:
2023-12-10
Revision Accepted:
2024-06-17
Crosschecked:
2024-09-09