GALNT14介导异常O-糖基化调控乳腺癌侵袭转移的分子机制

Breast cancer is the most common malignancy in women. Invasion and metastasis are main factors which impact therapeutic effects of breast cancer. It is found that tumor invasion and metastasis are closely related to abnormal O-glycosylation. So it is of great scientific significance to clarify the mechanism of O-glycosylation mediated by glycosyltransferases regulating tumor invasion and metastasis. GALNT14 is one of N-acetylgalactosaminyltransferase family memebers. In our previous research, we found that GALNT14 was overexpressed in breast cancer tissue and promoted EMT, invasion and migration of breast cancer cells. However，the underlying mechanism is not clear. Here, we propose that abnormal spatio-temporal expression GALNT14 contributes to abnormal O-glycosylation of substrates, which affects cell polarity and induces EMT, invasion and metastasis of breast cancer. So we plan to study the subcellular location of GALNT14 and its correlation with invasion and metastasis, and the effect on cell polarity by using immunofluorescence and immunoelectronic microscope on one hand, and identify some novel substrates of GALNT14 and determine its regulatory effects on the other hand. We will try to elucidate the molecular mechanism of abnormal O-glycosylation regulated by GALNT14 promoting in breast cancer invasion and metastasis, with the hope to explore novel targeting therapeutics for breast cancer.

乳腺癌是女性常见恶性肿瘤，侵袭转移是影响治疗效果的主要因素。肿瘤侵袭转移与异常O-糖基化密切相关，因此，阐明糖基转移酶介导的异常O-糖基化对乳腺癌侵袭转移的调控机制具有重要科学意义。N-乙酰半乳糖胺转移酶14(GALNT14)是负责O-聚糖合成的起始酶之一。我们发现该酶不仅在乳腺癌高表达，还能促进乳腺癌上皮-间质转化（EMT）及侵袭迁移过程，但调控机制尚不清楚。在此我们提出GALNT14异常时空表达造成底物O-糖基化异常，可能影响细胞极性，促进乳腺癌EMT及侵袭转移。为此，我们一方面拟利用免疫电镜、免疫荧光研究GALNT14亚细胞定位与侵袭转移相关性、糖链异常修饰对细胞极性影响；另一方面通过凝集素印记、液质联用技术鉴定GALNT14新底物并明确其调控作用，阐明GALNT14介导异常O-糖基化调控乳腺癌侵袭转移的分子机制，为加深O-糖基化对肿瘤转移调控机制的理解奠定基础并为治疗提供新靶点。

乳腺癌侵袭转移与异常O-糖基化密切相关，阐明糖基转移酶介导的异常O-糖基化对乳腺癌侵袭转移的调控机制具有重要科学意义。N-乙酰半乳糖胺转移酶14(GALNT14)是负责O-聚糖合成的起始酶之一。前期工作中，我们发现GALNT14不仅在乳腺癌高表达，还能促进乳腺癌上皮-间质转化（EMT）及侵袭迁移过程，但具体调控机制尚不清楚。本课题以GALNT14为研究对象，发现GALNT14异常时空表达造成底物O-糖基化异常，调控极性蛋白的定位进而影响细胞极性，促进乳腺癌EMT及侵袭转移；鉴定得到GALNT14的新底物EFEMP2及GRP78，发现GALNT14能够通过糖基化修饰调节EFEMP2及GRP78对侵袭迁移能力；同时发现GALNT14调控乳腺癌的耐药性。本项目阐明了GALNT14介导异常O-糖基化调控乳腺癌侵袭转移的分子机制，为加深O-糖基化对肿瘤转移调控机制的理解奠定基础并为治疗提供新靶点。延伸并拓展研究了OGA介导的去糖基化在DNA损伤修复中的作用。