前列腺癌发生发展相关重金属促瘤机制研究

The severity and detrimental effects of heavy metal contamination become increasingly prominent. Its effects on tumorigenesis draw much attention. Exposure to heavy metals (cadmium, arsenic) has been shown to be associated to the development and progression of prostate cancer (PCa). We previously found that serum levels of chromium, nickel, and antimony were significantly elevated in patients with PCa compared with that in healthy controls. Low-dose exposure to antimony substantially strengthened the proliferative and invasive capacities of PCa cells in vivo and in vitro. It has been demonstrated that continuous exposure to cadmium initiates PCa. Whereas the role of PCa-related high-risk heavy metal in tumorigenesis remains to be clarified. It has been proposed that heavy metals could promote liver cancer progression by multiple mechanisms including DNA damage and energy metabolism disturbance. Whether such mechanisms account for the effects of high-risk heavy metals on the development and progression of PCa is unclear. Accordingly, our program focuses on 1) defining internal exposure profile for PCa, 2) studying PCa-promoting effects of low-dose exposure of heavy metals, 3) determining PCa-associated high-risk heavy metals, and 4) revealing molecular pathogenesis of high-risk heavy metal-induced development and progression of PCa. This study aims to provide scientific basis for understanding the tumor effects of heavy metal contamination and elucidating the etiology of PCa.

重金属污染的严重性及危害性日益突出，其肿瘤效应倍受关注。研究显示，镉及砷等暴露与前列腺癌（PCa）的发生发展密切相关。我们研究发现，PCa患者血清中铬、镍及锑的含量增高；低剂量锑暴露可促进PCa细胞增殖和侵袭。另有研究证实，镉暴露可诱发PCa。但PCa高风险重金属及低剂量下其肿瘤效应仍不完全清楚。项目组研究提示，低剂量锑可能通过CtBP2介导的通路促进PCa进展。另有研究发现，重金属促进肝癌等肿瘤进展的效应可能通过DNA损伤、能量代谢紊乱等多种机制实现。高风险重金属是否通过上述机制促进PCa的发生发展，目前尚不明确。据此，本项目以重金属内暴露为切入点，重点研究：①明确PCa的重金属内暴露谱；②解析重金属低剂量暴露的前列腺肿瘤效应；③明确PCa发生发展相关的高风险重金属；④揭示高风险重金属促进PCa发生发展的分子机理。本项目的开展将为认识重金属污染的肿瘤效应及揭示PCa病因学提供科学依据。

重金属污染的严重性及危害性日益突出，其肿瘤效应倍受关注。研究显示，镉及砷等暴露与前列腺癌（PCa）的发生发展密切相关。我们研究发现，PCa患者血清中铬、镍及锑的含量增高；低剂量锑暴露可促进PCa细胞增殖和侵袭。另有研究证实，镉暴露可诱发PCa。但PCa高风险重金属及低剂量下其肿瘤效应仍不完全清楚。项目组研究提示，低剂量锑可能通过CtBP2介导的通路促进PCa进展。另有研究发现，重金属促进肝癌等肿瘤进展的效应可能通过DNA损伤、能量代谢紊乱等多种机制实现。高风险重金属是否通过上述机制促进PCa的发生发展，目前尚不明确。据此，本项目以重金属内暴露为切入点，重点研究：①明确PCa的重金属内暴露谱；②解析重金属低剂量暴露的前列腺肿瘤效应；③明确PCa发生发展相关的高风险重金属；④揭示高风险重金属促进PCa发生发展的分子机理。本项目研究发现：重金属铬与锑高水平均与前列腺癌患者不良预后相关；重金属锑可通过CtBP2-ROCK1通路促进前列腺癌细胞增殖；锑通过类雄激素效应促进激素依赖性前列腺癌细胞增殖；铬通过EMT通路促进前列腺癌细胞转移；本项目的开展将为认识重金属污染的肿瘤效应及揭示PCa病因学提供科学依据。