Musashi2/Numb在胰腺癌侵袭和转移中的作用及机制研究

Pancreatic cancer (PC) is one of the most malignant digestive tumors with a total 5-year survival rate less than 5%. The poor prognosis is mainly due to its strong local invasion and distant metastasis in early stage. It is significant for detecting tumor biomarkers and gene targets based on understanding the molecular mechanism of invasion and metastasis in PC. Musashi2/Numb coordinately participates in the development and progression of leukemia. However, this regulation remains controversial in previous studies and has been rarely reported in solid cancers. Moreover, the corresponding molecular mechanism remains unclear. Our previous study showed that Musashi2 promoted invasion and metastasis of PC cells by down-regulating Numb protein. Based on PCR microarray and subsequent experiment, we infer Musashi2 post-transcriptionally regulates Numb protein through binding its RRM domain to 3’UTR of Numb. Numb downregulaton enhances MDM2-mediating degradation of p53 in ubiquitin-proteasome system, decreases the combination of p53 and MT2A promoter region, inhibits MT2A transcription, disregulates MT2A and its downstream signal pathway, and finally promotes PC invasion and metastasis. Systematically clarifying the mechanism of Musashi2/Numb in regulating invasion and metastasis of pancreatic cancer is meaningful for inhibiting tumor malignant progression by gene targets and improving the prognosis of PC patients.

胰腺癌是人类消化系统恶性度最高的肿瘤之一，5年总体生存率始终低于5%。预后差归因于其早期易发生胰周侵袭和远处转移。深入研究胰腺癌侵袭及转移的分子机制，寻找新的肿瘤标记物及分子治疗靶点至关重要。Musashi2/Numb共同参与白血病的发生进展，但这种调控方式上尚存争议，在实体肿瘤中鲜有报道，分子机制仍不清楚。我们前期工作发现Musashi2通过下调Numb蛋白调控胰腺癌细胞侵袭和转移。运用基因芯片以及后续实验推测，MSI2通过自身RRM域与Numb 3’UTR区相结合，转录后水平调控Numb蛋白，Numb下调使MDM2对p53泛素化降解加强，p53与MT2A启动子区结合减少，MT2A转录受抑，MT2A及其下游信号通路失活，最终促进胰腺癌的侵袭和转移。本课题通过阐明Musashi2/Numb调节胰腺癌侵袭和转移的分子机制，对运用基因靶向治疗抑制肿瘤恶性进展，改善胰腺癌患者的预后具有重要意义。

胰腺癌是人类消化系统恶性度最高的肿瘤之一，5年总体生存率始终低于5%。预后差归因于其早期易发生胰周侵袭和远处转移。深入研究胰腺癌侵袭及转移的分子机制，寻找新的肿瘤标记物及分子治疗靶点至关重要。Musashi2/Numb在实体肿瘤中研究鲜有报道，分子机制仍不清楚。本课题推测，MSI2通过自身RRM域与Numb 3’UTR区相结合，转录后水平调控Numb蛋白，Numb下调使MDM2对p53泛素化降解加强，p53与MT2A启动子区结合减少，MT2A转录受抑，MT2A及其下游信号通路失活，最终促进胰腺癌的侵袭和转移。经过历时四年的研究，我们团队围绕MSI2-Numb核心通路，从胰腺癌分子标记物在增殖凋亡及耐药、侵袭/转移，及临床病理学意义中的作用，发表多篇相关论著。我们首先发现MSI2作为Numb上游癌基因，负向调控Numb，促进胰腺癌增殖侵袭和迁移（Oncotarget. 2017, 28;8(9):14359-14373）。进一步研究发现，化疗药物诱导下，MSI2通过正向调控MDM2，负向调控Numb和p53，促进胰腺癌耐药（FASEB J. 2017;31(6):2429-2438）。同样地，SPRK2作为Numb上游癌基因，通过下调p53和Numb，促进胰腺癌耐药和侵袭（FEBS J. 2019;286(9):1668-1682）。最后，以MSI2为核心，我们拓展性研究发现，MSI2通过上调EMT转录因子ZEB-1，同时促进EGR磷酸化（酪氨酸1068）,激活ERK/MAPK通路，促进EGF诱导胰腺癌EMT发生（J Exp Clin Cancer Res. 2020;39(1):167）。同时，MSI2通过调控肌醇相关蛋白ISYNA11以及p21/ZEB-1，促进胰腺癌增殖迁移（J Cell Mol Med. 2020;24(18):10560-10572.）。MT2A通过与p53相互作用，协同调控胰腺癌的侵袭、迁移增殖和耐药。本课题目前共发表SCI论著5篇，其中1区1篇，2区4篇，中文核心期刊2篇，系统阐明MSI2/Numb在胰腺癌发生发展中作用及多种分子机制，为胰腺癌患者基因靶向治疗奠定理论基础。