含氧多环芳烃促肝癌细胞侵袭转移过程中Hippo通路作用探究  

Role of Hippo pathway in promoting invasion and metastasis of liver cancer cells by oxygenated polycyclic aromatic hydrocarbons

作　　者：高瑞 武秀瑜 蔡知洪 桑楠[2] GAO Rui;WU Xiuyu;CAI Zhihong;SANG Nan(School of Forensic Medicine,Shanxi Medical University,Jinzhong,030600,China;College of Environmental and Resource Sciences,Shanxi University,Taiyuan,030006,China)

机构地区：[1]山西医科大学法医学院,晋中030600 [2]山西大学环境与资源学院,太原030006

出　　处：《环境化学》2024年第4期1118-1126,共9页Environmental Chemistry

基　　金：国家自然科学基金(22106097);山西省基础研究计划青年项目(20210302124059);山西省高等学校科技创新项目资助。

摘　　要：由于氧化官能团的存在,含氧多环芳烃(oxy-PAHs)比母体多环芳烃具有更高的极性、溶解度、迁移率和生物反应活性,在环境中的分布更为广泛.许多oxy-PAHs具有更高的遗传毒性、促肿瘤活性和发育毒性,而目前关于其促肿瘤活性作用机制的研究较少.Hippo-YAP通路被发现是调节癌细胞免疫、增殖、转移等的关键因子.本研究基于肝癌细胞暴露模型,对环境含量丰富的含氧多环芳烃(9-芴酮)的促肿瘤作用及Hippo-YAP调控机制进行了探究.结果发现,较高浓度9-芴酮(9-Fluorenone)暴露可促进肝癌细胞侵袭、迁移及上皮间质转化(EMT)的发生,且Hippo-YAP通路在9-Fluorenone促肿瘤过程中有重要作用.具体而言,9-Fluorenone暴露可通过诱导Hippo上游激酶MST、LATS以及YAP蛋白的去磷酸化,未磷酸化的YAP可以直接进入细胞核内与TEAD结合,调控下游EMT的发生,进而促进侵袭转移.本研究结果为含氧多环芳烃的促肿瘤活性研究提供了实验基础,对于全面评估多环芳烃及衍生物的生态和健康风险具有重要参考作用.Due to the presence of oxygenated functional groups,oxygenated polycyclic aromatic hydrocarbons(oxy-PAHs)possess higher polarity,solubility,mobility,and biological reactivity than their parent PAHs,and are more widely distributed in the environment.Although numerous oxy-PAHs exhibit heightened genotoxicity,carcinogenicity,and developmental toxicity,limited research has been conducted to elucidate the underlying mechanisms responsible for their tumorigenic promotion.Notably,the Hippo-YAP pathway has emerged as a pivotal regulatory process governing cancer cell immunity,proliferation,and metastasis.In this study,the tumor promoting effect of oxy-PAHs(specifically 9-Fluorenone)that are commonly found in the environment,as well as the underlying Hippo-YAP regulation mechanism were investigated by using the liver cancer cell exposure model.The results showed that a high concentration of 9-Fluorenone exposure significantly enhanced the invasion,migration,and epithelial-mesenchymal transition(EMT)of HepG2 cells,and the Hippo-YAP pathway was identified as playing a crucial role in the tumor-promoting process.Specifically,9-Fluorenone exposure can induce dephosphorylation of upstream kinases in the Hippo pathway,such as MST and LATS,and then induce dephosphorylation of YAP.Consequently,YAP is able to bind to TEAD in the nucleus,thereby regulating the occurrence of EMT and ultimately promoting the invasion and metastasis of cancer cells.This study contributes valuable toxicological evidence supporting the tumor-promoting effect of oxy-PAHs and holds significant reference value for the comprehensive assessment of the ecological and health risks associated with PAHs and their derivatives.

关 键 词：含氧多环芳烃 侵袭转移 HIPPO EMT 

分 类 号：X503[环境科学与工程—环境工程] X592