癌基因STOML2诱导基因组不稳定及促肿瘤发生的分子机制

虽然已明确基因组不稳定与肿瘤的发生密切相关，然而导致基因组不稳定，诱导正常细胞永生化，促使细胞恶性转化成为肿瘤干(起始)细胞的关键节点及调控机制，目前仍不清楚。我们前期发表文章报道癌基因STOML2与肿瘤的发生发展密切相关。近期我们预实验数据显示：STOML2可通过①促进细胞DNA损伤，②抑制DNA损伤修复能力，③诱导中心体扩增而形成异倍体细胞等多种机制促使正常细胞基因组不稳定；进一步结合生物信息学及生物学实验结果，我们发现高表达STOML2可上调多个与细胞早期转化相关基因并延长正常细胞生长寿命期；并且高表达STOML2还可增强细胞的肿瘤干细胞特性并促进细胞恶性转化及活体成瘤率。这些结果表明癌基因STOML2是肿瘤发生的关键分子。本项目将承前启后，采用体内体外系统，并与临床相结合，深层次解析癌基因STOML2网络调控基因组不稳定与诱导肿瘤发生的分子机制，为肿瘤的诊断治疗提供新的靶位点。

It has been demonstrated that genomic instability (GIN) is strongly associated with tumorigenesis. However,, the precise mechanisms and key factors that are involved in promoting genomic instability, inducing normal cell immortalization, provoking malignant transformation and the formation of tumor initiating cells (cancer stem cells) remain largely unclear. Previously, we have reported that the oncogene STOML2 plays important roles in the development and progression of cancer (Journal of Pathology, 2012;226:534-43). Our recent preliminary data showed that the upregulation of STOML2 led to genomic instability in normal cells through multiple mechanisms, including the promotion of DNA damage, the inhibition of DNA damage repair and the induction of centrosome amplification that resulted in the formation of aneuploid cells. Furthermore, by integrating the results obtained from bioinformatic analysis and biological experiments, we found that the overexpression of STOML2 extended the lifespan of normal cells by upregulating several genes related to immortalization. Moreover, the ectopic expression of STOML2 also augmented the stem cell characteristics of tumor cells, promoted cellular malignant transformation and enhanced tumor formation in nude mice. These results suggest that STOML2 might be a key factor in tumorigenesis. Hence, in the current project, we used in vivo and in vitro systems combined with clinical samples to investigate the mechanisms of STOML2-induced genomic instability and tumorigenesis, which could provide a new target for tumor diagnosis and treatment.