“老化的”纳米ZnO协同激活突变SHP-2促进小鼠胚胎成纤维细胞恶性转化及机制探讨

Malignant tumor is most harmful to human. The occurrence of most malignant tumor keeps rising and more young people is being implicated. The mechanism of carcinogenesis is much complicated with interact of environmental and genetic factors. Engineered nanoparticles belong to a new kind of environmental pollutants which could be widely exposed to human. Although its genotoxicity and mutagenecity was investigated and conformed, its carcinogenesis still remains unidentified. Our previously study showed that compared to "fresh" ZnO-NPs, "aged" ZnO-NPs could induce higher degree of DNA damage and choromosome mutation. We deduced that the ignorance of the effects of environmental factors on nanoparticles and the lack of synergistic effect with inner genetic factors (mutation) could be the two main possible reasons for the uncertainty of carcinogenesis of nanoparticles. Our research team has always been committed to the study on the relationship between mutagenecity and the occurrence and progression of malignant tumors. Our preliminary data suggested that gain-of-function mutant SHP-2 might be involved in carcinogenesis induced by environmental pollutants. Here, we will apply the well-generated mutant SHP-2 knock-in MEFs model to our research on the carcinogenesis of ZnO-NPs, to investigate whether the "aged" ZnO-NPs coupled with SHP-2 mutation could enhance malignant transformation of our mutant SHP-2 knock-in MEFs and try to explore the molecular mechanisms in it. The results obtained from this project will elucidate the role of mutant SHP-2 in nanoparticles-induced carcinogenesis promotion and identify novel targets for mechanism research of tumorigenesis.

恶性肿瘤严重危害人类健康且呈高发早发趋势，其发病机制复杂且尚未被阐明，目前认为可能是环境和遗传因素共同作用的结果。纳米材料作为被人类广泛接触到的新型环境污染物，已被证实可致DNA损伤和基因突变，但其致/促癌性目前尚无定论。我们前期研究发现相比于“新鲜的”纳米ZnO，“老化的”纳米ZnO遗传毒性更强，同时本课题组也证实含有SHP-2酪氨酸磷酸酶激活突变的细胞及小鼠在重金属等环境因素诱导下更容易恶性转化及高发肿瘤，“老化的”纳米ZnO也更容易诱导SHP-2激活突变的小鼠MEFs集落形成，因此，我们推测“老化的”纳米ZnO可能协同SHP-2激活突变促进细胞恶性转化及肿瘤发生。本课题拟用不同环境因素影响下“老化”状态的ZnO-NPs作用于激活突变的MEFs及小鼠模型，检测细胞生物学行为的改变及小鼠肿瘤发生情况，并探讨其分子机制，为纳米材料促癌致癌研究提供线索，为肿瘤高发早发的机制研究提供新的思路。

恶性肿瘤严重危害人类健康且呈高发早发趋势，其发病机制复杂且尚未被阐明，目前认为 可能是环境和遗传因素共同作用的结果。纳米材料作为被人类广泛接触到的新型环境污染物， 已被证实可致DNA损伤和基因突变，但其致/促癌性目前尚无定论。我们前期研究发现相比于“ 新鲜的”纳米ZnO，“老化的”纳米ZnO遗传毒性更强，同时本课题组也证实含有SHP-2酪氨酸磷酸酶激活突变的细胞及小鼠在重金属等环境因素诱导下更容易恶性转化及高发肿瘤，“老化 的”纳米ZnO也更容易诱导SHP-2激活突变的小鼠MEFs集落形成，由此我们推测“老化的”纳米ZnO可能协同SHP-2激活突变促进细胞恶性转化及肿瘤发生。结果本课题的实施证实了我们的推测。利用前期研究获得的 “老化”状态的ZnO-NPs作用于激活突变的MEFs，我们发现：经低剂量“ 新鲜的”纳米ZnO和“老化的”纳米ZnO慢性诱导之后的MEF细胞，其恶性生物行为显著增强，并能在裸鼠中成瘤；SHP-2基因突变都对上述研究终点呈现促进作用；在恶性转化过程中ROS活化的ERK信号途径参与调控。本项目研究结果为纳米材料促癌致癌研究提供线索，为肿瘤高发早发的机制研究提供新的思路。