N-乙酰基半乳糖胺转移酶6调控粘蛋白13的O-糖基化参与卵巢癌进展的作用研究

Aberrantly expressed glycotransferase catalyzed altered glycosylation which has a key role in the proliferation, invasion, migration, immune evasion and chemoresistance of tumor cells. The applicant has investigated the molecular mechanisms and functional roles of altered N-linked, O-linked, and terminal glycosylation of glycoprotein and downstream p21 activated kinase-1 (PAK1) activation in the tumorigenesis of hepatocarcinoma and renal carcinoma, which had been published by Cancer Res 2011, Gastroenterology 2012, Glycobiology 2013, and J Biol Chem 2015. We have identified that the expression of polypeptide N-acetygalactosaminyl transferase 6 (GALNT6) was increased in ovarian cancer tissues compared with the normal ovarian tissues and correlated with deteriorated tumor cell differentiation and advanced FIGO stage and reduced overall survival and recurence free survival. GALNT6 expression was positively correlated with the expression of Mucin-13 in ovarian cancer cell lines. Reduced GALNT6 expression inhibited the interaction between Mucin-13 and epithelium growth factor receptor (EGFR). The aim of this project is to further elucidate the structure and functional role of O-linked glycosylation of Mucin-13, the molecular mechanism and therapeutic model for GALNT6 induced Mucin-13 O-glycosylation and increased interaction with EGFR and activation of PAK1 signaling pathway. Therefore the results of the project will lay the foundation for early detection and development of target therapeutic strategies of ovarian cancer.

糖基转移酶异常介导的糖链结构改变参与肿瘤增殖、侵袭转移、免疫逃逸和耐药。项目申请人发现异常N-糖基化、O-糖基化和末端糖基化修饰蛋白及下游PAK1通路活化在肝癌和肾癌发生发展中发挥关键作用(Cancer Res 2011，Gastroenterology 2012，Glycobiology 2013，J Biol Chem 2015)。我们前期研究发现O-糖基化修饰相关N-乙酰基半乳糖胺转移酶6(GALNT6)在卵巢癌中高表达与肿瘤进展相关，下调GALNT6表达抑制粘蛋白13(MUC13)和表皮生长因子(EGFR)的相互作用。本项目拟在前期研究基础上进一步解析MUC13的O-糖链结构特征和功能意义，阐明GALNT6通过调控O-糖基化修饰MUC13促进EGFR膜表面定位及下游PAK1通路活化参与卵巢癌进展的分子机制，为卵巢癌早期诊断和开发靶向针对异常O-糖基化修饰的个体化治疗药物奠定基础。

在本项目资助下，项目负责人围绕糖基转移酶与肿瘤侵袭、转移及肿瘤微环境研究领域展开研究工作并取得了一系列研究成果，以第一作者在Nature Communications、Journal of Biological Chemistry，通讯作者在Cancer Immunology Immunotherapy, Cancer Chemotherapy and Pharmacology, Journal Gynecol Oncol等肿瘤学和妇产科学国际权威期刊发表11篇SCI 论文。我们发现GALNT4低表达可以通过活化EGFR信号通路促进肿瘤进展和肿瘤干细胞样特性，miR-9通过靶向GALNT4抑制其表达促进肿瘤进展(J Biol Chem 2017)，我们还发现EZH2-miR-622-CXCR4信号通路异常活化上调CXCR4表达，靶向抑制CXCL12-CXCR4轴抑制肿瘤生长，发挥抗肿瘤效应（Nature communications, 2015），该研究首次提出了CXCR4的表观调控机制，为CXCR4高表达的肿瘤患者提供了新的治疗靶点。卵巢高级别浆液性腺癌组织中GALNT10高表达患者预后不良，其肿瘤呈现免疫抑制微环境，其中发挥抗肿瘤效应的CD3 T细胞和NK细胞数量减少，发挥促进免疫逃逸的Treg细胞和M2巨噬细胞数量增加（Cancer Imnmuology Immunotherapy, 2020），该研究首次确认GALNT10与肿瘤免疫抑制微环境相关。PARP抑制剂奥拉帕尼靶向BRAC1/2突变卵巢癌患者，但获得性耐药影响了奥拉帕尼的疗效，研究发现奥拉帕尼小剂量长时间处理诱导卵巢癌细胞衰老相关表型（Journal of Gynecologic Oncology, 2019），而PPAR-γ抑制剂罗格列酮能逆转奥拉帕尼诱导的衰老相关表型，促进卵巢癌细胞凋亡，抑制肿瘤生长（Cancer Chemotherapy and Pharmacology,2020），该研究为卵巢癌患者PARP靶向治疗提供了新的治疗策略。