MCM5激活Notch通路并调控非小细胞肺癌干性和侵袭转移的分子机制研究

Presence of cancer stem cell and Epithelial mesenchymal transition-induced invasion are essential to recurrence, metastasis, as well as worse prognosis of non-small cell lung cancer (NSCLC). While it has been well accepted that Notch signaling is important to the above traits, mechanisms underlying its activation in NSCLC remains to be further clarified. Our previous works have shown that MCM5 interacted with notch intra-cellular domain (NICD) in nuclei, repressed its degradation and activated Notch pathway. We found MCM5 up-regulated miR-182, and miR-182 can inhibited protein expression of NUMB (located in cytoplasm) and FBXW7 (located in nuclei), two negative regulators of Notch signaling. Moreover, we also found that MCM5 was enhanced in NSCLC and promoted stemness as well as metastasis-related traints of cancer cells. In the current project, we will systematically investigate the mechanism of MCM5’s multiple sub-cellular regulation in triggering Notch signaling, and how it promotes NSCLC malignancy. Moreover, we will further clarify how the key modulators change in tumor specimens thus provide new targets for diagnosis and prognosis of NSCLC.

肿瘤干细胞的存在及上皮间质转化诱导侵袭的发生是非小细胞肺癌复发、转移及低生存率的重要原因。Notch通路异常激活在其中起重要作用，但其激活的分子机制仍不甚清楚。我们前期研究发现：MCM5可与核内Notch胞内段（NICD）结合、抑制其降解并激活Notch通路；MCM5还可上调miR-182，而后者能抑制Notch通路负性调控分子（核外NUMB及核内FBXW7）的蛋白表达；另外，我们还发现MCM5在非小细胞肺癌中升高并可促肿瘤细胞干性维持和侵袭转移。本项目将承前启后，在非小细胞肺癌中深入解析MCM5直接通过结合核内NICD，从而竞争性抑制NICD泛素化降解；以及间接通过促miR-182转录，从而增强其对Notch通路负性调控分子的靶向抑制，最终在不同亚细胞层面实现对Notch通路的激活并促肿瘤干性维持和侵袭转移。且将在临床标本上探讨以上关键分子与非小细胞肺癌临床的关系，为诊断预后提供新靶点。

肿瘤干细胞的存在及上皮间质转化诱导侵袭的发生是非小细胞肺癌复发、转移及低生存率的重要原因。Notch通路异常激活在其中起重要作用，但其激活的分子机制仍不甚清楚。我们的研究在非小细胞肺癌中发现MCM5直接通过结合核内NICD，从而竞争性抑制NICD泛素化降解；以及间接通过促miR-182转录，从而增强其对Notch通路负性调控分子的靶向抑制，最终在不同亚细胞层面实现对Notch通路的激活并促肿瘤干性维持和侵袭转移。我们还发现MCM5的表达升高与其mRNA上发生了IGF2BPs介导的m6A修饰相关。研究将为非小细胞肺癌的诊断预后提供新靶点。