Chen Jiongyu, Zhou Zhangzhu, Lin Xueqiong, Liao Jiahui, Zhang Yujie, Xie Bingmeng, Huang Yiteng, Peng Lin
Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, China.
Department of Laboratory, Jiangmen Central Hospital, Jiangmen, China.
Front Cell Dev Biol. 2022 Feb 18;10:792933. doi: 10.3389/fcell.2022.792933. eCollection 2022.
Cadmium (Cd) exposure has been implicated in the etiology of esophageal squamous cell carcinoma (ESCC), albeit with inconsistent results from epidemiologic studies and without causal evidence. In this study, we explore the relationship of Cd exposure and the development, progression and therapeutic resistance of ESCC. A total of 150 ESCC patients and 177 matched controls from a coastal region with a high incidence of ESCC in China were included in the study. It was found that the median blood Cd level (BCL) was significantly higher in ESCC patients than that in the controls. Odds ratios for ESCC risk were 3.12 (95% CI 1.54-6.30) and 3.71 (95% CI 1.84-7.48) in the third and fourth quartiles of Cd distribution, respectively. Notably, BCL above 4.71 μg/L was strongly associated with shorter progression-free survival time compared to that below 1.60 μg/L ( < 0.001). The chronic Cd-treated ESCC cells (CCT-ESCC) CCT-EC109 and CCT-EC9706 exhibited increased cell proliferation and tumorigenesis, enhanced migration and invasion, and upregulated EMT biomarkers following 12 weeks of exposure to 5 μM cadmium chloride. Furthermore, Cd treatment attenuated the efficacy of 5-fluorouracil, cisplatin and irradiation treatment in CCT-ESCC cells both and . Moreover, we revealed that Cd stimulated the cancer cell stemness and Wnt/β-catenin signaling pathway in the CCT-ESCC cells. Additionally, 5-aza-2-deoxy-cytidine treatment resulted in suppression of the Wnt/β-catenin signaling pathway and rescue of the Cd-induced cell radioresistance. These results offer new insights into the role of environmental Cd exposure in the development, progression and chemoradioresistance of ESCC.
镉（Cd）暴露与食管鳞状细胞癌（ESCC）的病因有关，尽管流行病学研究结果不一致且缺乏因果证据。在本研究中，我们探讨了Cd暴露与ESCC发生、发展及治疗耐药性之间的关系。本研究纳入了来自中国食管癌高发沿海地区的150例ESCC患者和177例匹配对照。结果发现，ESCC患者的血液镉水平（BCL）中位数显著高于对照组。在Cd分布的第三和第四四分位数中，ESCC风险的优势比分别为3.12（95%CI 1.54 - 6.30）和3.71（95%CI 1.84 - 7.48）。值得注意的是，与低于1.60μg/L的情况相比，BCL高于4.71μg/L与无进展生存期缩短密切相关（<0.001）。经慢性镉处理的ESCC细胞（CCT - ESCC）CCT - EC109和CCT - EC9706在暴露于5μM氯化镉12周后，细胞增殖和肿瘤发生增加，迁移和侵袭增强，上皮 - 间质转化（EMT）生物标志物上调。此外，镉处理减弱了5 - 氟尿嘧啶、顺铂和放疗对CCT - ESCC细胞的疗效。而且，我们发现镉刺激了CCT - ESCC细胞中的癌细胞干性和Wnt/β - 连环蛋白信号通路。此外，5 - 氮杂 - 2'-脱氧胞苷处理导致Wnt/β - 连环蛋白信号通路受到抑制，并挽救了镉诱导的细胞放射抗性。这些结果为环境镉暴露在ESCC发生、发展和放化疗耐药中的作用提供了新的见解。
