六价铬 Cr(VI) 是一种公认​​的致癌物质，有助于许多人类癌症的发生，特别是呼吸道和消化道肿瘤。然而，Cr(VI)在食管癌发生中的潜在功能和相关机制尚不清楚。在此，永生化人食管上皮细胞（HEEC）通过长期暴露于 Cr(VI) 被诱导成为恶性转化细胞，称为 HEEC-Cr(VI) 细胞，这模拟了食管肿瘤发生的过程。体外和体内实验表明，与 BALB/c 裸鼠相比，HEEC-Cr(VI) 细胞具有贴壁独立生长能力、更强的增殖能力、癌症干细胞特性以及形成皮下异种移植物的能力。亲代细胞，HEEC。此外，HEEC-Cr(VI)细胞表现出细胞运动减弱和细胞粘附增强。有趣的是，急性暴露于 Cr(VI) 的 HEEC 未能表现出 HEEC-Cr(VI) 细胞的恶性表型，这表明 Cr(VI)‍ 诱导的恶性转化，而不是 Cr(VI) 本身，是导致恶性转化的原因。 HEEC-Cr(VI)细胞的肿瘤特征。从机制上讲，长期接触 Cr(VI) 会诱导 Notch 信号传导异常激活，这对于维持 HEEC-Cr(VI) 细胞的恶性增殖和干细胞能力至关重要。正如预期的那样，Notch 通路抑制剂 N-‍[N-‍(3,5-二氟苯乙酰基)‍-L-丙氨酰]‍-S-苯基甘氨酸叔丁酯 (DAPT) 可显着减弱 HEEC- 的癌表型。 Cr(VI) 细胞。总之，我们的研究阐明了Cr(VI)‍诱发食管肿瘤发生的分子机制，为Cr(VI)‍相关食管癌的进一步基础研究和临床治疗策略提供了新的见解。

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.