癌基因STOML2诱导基因组不稳定及促肿瘤发生的分子机制

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.

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。

前期我们已证明癌基因STOML2 在肿瘤的发生发展中具有重要的作用。 进一步（1）NF-kB可结合miR-138启动子而抑制STOML2及FLOT1表达。 深入研究发现：食管癌中miR-138显著下调，抑制miR-138可直接促进FLOT-1及STOML2表达升高，而调控膜受体近端复合体而激活NF-kB信号通路，为肿瘤NF-kB信号通路持续性激活提供了新的机制 (Clin Cancer Res. 2013. 通讯作者)。2. 进一步研究发现STOML2可与AKIP1蛋白相结合， 而核蛋白AKIP1可在细胞核内抑制IκB-α与NF-κB的结合，阻滞NF-κB因子的细胞核/浆转位，从而维持了NF-κB转录活性的持续时间及强度(Cancer Res. 2013. 通讯作者)。 3. 我们研究发现：STOML2 可通过NF-κB转录上调miR-508的表达而直接抑制了等多个磷酸酶，导致了PI3K/Akt信号通路组成性激活。重要的是，miR-508的水平与食管鳞状细胞癌患者生存不良及激活的PI3K/Akt信号相关。 这些研究结果揭示出了食管鳞状细胞癌中组成性PI3K/Akt激活的一个新机制，阐明了在癌症进展过程中一个功能性的与临床相关的表观遗传机制。 (Nature Communications. 2014. 共同通讯作者)。 4. 进一步研究发现STOML2可与AKIP1蛋白相结合， 而核蛋白AKIP1可在细胞核内抑制IκB-α与NF-κB的结合，阻滞NF-κB因子的细胞核/浆转位，从而维持了NF-κB转录活性的持续时间及强度， 并促进了食管癌淋巴结转移，以上研究结果为食管癌治疗提供了新的靶点 (Oncogene. 2014. 通讯作者)。5. 我们研究表明STOML2结合AGK在肝癌中显著增高并激活NF-kB信号通路而促进肝癌的血管增生及抗凋亡能力。(Oncotarget. 2014;共同通讯作者) 。6. STOML2结合蛋白GOLPH3与TNFa受体相结合而促进NF-kB通路分子TRAF2/RIP1/NEMO K-63泛素化而激活NF-kB通路。并且GOLPH3蛋白表达与肝癌患者的不良预后密切相关。高表达GOLPH3可激活NF-kB信号通路并促进肝癌凋亡及血管增生 (J Pathol. 2015; 235: 490–501. 共同通讯作者)。