镉暴露与鼻咽癌发生发展及放射抗拒相关机制

Cadmium is a ubiquitous carcinogenic pollutant. The association between cadmium and nasopharyngeal carcinoma(NPC) remains unclear . We previously reported for the first time that cadmium burden might be not only a risk of NPC, but also positively associated with node classification and clinical stage. Recently, we performed experiments in vitro and found that cadmium exposure could induce NPC cells proliferation, invasion, migration and radio-resistance. However，the mechanisms remain unknown. PTEN-AKT/mTOR pathway has been implicated in proliferation and metastasis of NPC, among which PTEN acted as a negative regulatory. Now we speculated that cadmium decreased PTEN expression via promoter hypermethylation, then AKT/mTOR signaling pathway was activated and promote cell proliferation, metastasis and radio-resistance. This project will carry out a large-scale case-control study with multi-exposure biomarkers of cadmium. And based on the establishment of NPC cell models of chronic low-dose cadmium exposure, we will perform a further and systematic study, including in vitro and in vivo, to explore the relationships between cadmium exposure and NPC occurrence, development and radio-resistance. Also, we will try to apply siRNA, demethylation, specific inhibitors of pathway to reveal the function and regulation of PTEN-AKT/mTOR signaling involved in it. It maybe provide a new theoretical basis for NPC etiology and radio-resistance study.

镉是一类广泛存在的环境致癌物，与鼻咽癌的关系尚不明确。我们前期人群研究首次指出，镉负荷不仅可能是NPC的危险因素，且与淋巴结转移、临床分期相关。最近我们通过体外实验初步证实，镉暴露可促进NPC细胞增殖、侵袭和迁移，诱导放射抗拒。近年发现PTEN-AKT/mTOR信号通路参与NPC的增殖和转移，其中PTEN是负调控因子。慢性镉暴露是否通过诱导PTEN基因高甲基化致表达下降，激活AKT/mTOR信号通路继而促细胞增殖、转移及放射抗拒，值得探索。本项目将进一步开展大样本、多种暴露标志物的病例-对照研究；并在已建立的慢性镉暴露NPC细胞模型基础上，通过系列体内外实验，深入探讨镉暴露与NPC发生、发展及放射抗拒的关系；同时应用siRNA、去甲基化、信号通路抑制等方法，明晰PTEN-AKT/mTOR通路在镉致癌机制中的作用和调控，从而为NPC病因学及放射抗拒研究提供新的理论依据。

镉是一类环境中广泛存在的Ⅰ类致癌物。流行病学和实验研究表明多种肿瘤与镉暴露有关，但慢性低剂量镉暴露与鼻咽癌发生、发展及放疗敏感性的关系，尚无报道。项目在前期病例-对照和病例-病例研究基础上，通过模拟非职业人群环境镉暴露条件，建立慢性低浓度镉暴露鼻咽癌细胞株，经系列体外、体内实验证实慢性镉暴露促进鼻咽癌细胞恶性演进，降低放射敏感性。Wnt/β- catenin信号通路被认为参与镉致肾癌机制，但具体调控不明确。甲基化修饰是镉致癌机制之一，本研究发现镉暴露鼻咽癌细胞酪蛋白激酶Ⅰα（CK1α）表达降低，甲基化水平升高，初步阐明镉暴露可通过诱导CK1α DNA甲基化激活Wnt/β-catenin信号通路，从而促进鼻咽癌细胞生长、侵袭转移及放疗抵抗镉。病例随访研究尚未发现镉负荷影响鼻咽癌患者总生存期。课题组还对镉暴露与食管癌发生、发展的关系进行初步探讨，发现镉暴露也能促进食管癌演进及放化疗抵抗。此外，通过体内外实验证实中药蛇床子素具有提高鼻咽癌放射敏感性的作用，下一步拟探讨蛇床子素作为逆转镉诱导肿瘤放疗抵抗潜在药物的可能。项目的完成为镉的致癌作用及NPC病因学、放疗抵抗研究提供新的思路和理论依据。