醣脂質(Glycosphingolipids,簡稱GSLs)是一種表現在細胞膜上的醣化脂類，當中globo-series的GSLs在癌細胞中高度或專一表達，因此可被當作精準治療或診斷之標的。其中階段特異性胚胎抗原3(Stage specific embryonic antigen 3, 簡稱SSEA3)；唾液酸化階段特異性胚胎抗原4 (簡稱 SSEA4)；岩藻醣化階段特異性胚胎抗原3 (簡稱Globo-H)更是高度表達在惡性組織中，在臨床上與疾病的進程有相當的正關聯性。在本研究中指出SSEA3不僅是細胞膜上的標記分子，並且促進許多訊息傳遞中酪氨酸激酶相關路徑的活化，在細胞內，主要是由GalNAcβ3Galα4Galβ4GlcβCer (簡稱Gb4)前驅物經酵素β1,3-半乳糖轉化酶第五型(簡稱β3GalT5)催化作用，接上beta 1,3鍵結的半乳糖而生成SSEA3 (別名Gb5)，進而衍生後續的SSEA4或Globo-H，所以β3GalT5是主要影響以上三種癌症關聯性醣脂表達之重要酵素，但是β3GalT5及SSEA3對於乳癌細胞扮演的功能性與訊息調控機制均尚未清楚了解。
因此本篇研究中，觀察乳癌病人之組織切片，在惡性腫瘤處發現有大量的β3GalT5表現，此外β3GalT5的表達與病人之疾病惡化程度及低存活率成高度正相關。當我們利用基因抑制的方法降低酵素β3GalT5的表達，同時使得細胞表面降低SSEA3的表現，造成乳癌細胞株MCF7及MDA-MB-231細胞生長減緩，也觀察到此現象導致乳癌細胞走向細胞凋亡路徑，此路徑證實是透過Fas及FADD下游引發caspase-3及caspase-8活化所主導的細胞凋亡，並且，在抑制β3GalT5與SSEA3表現的同時，也造成Focal adhesion kinase (FAK) 蛋白的減少，以致於抑制乳癌細胞爬行與貼附的能力。經過共同免疫沉降與免疫螢光染色的實驗，證實在細胞膜上脂筏區域，可以發現到SSEA3會與caveolin1 (CAV1)及FAK形成聚合體，推測SSEA3聚合體可以共同調控癌細胞的生長，更發現此SSEA3聚合體與Receptor-interacting protein (RIP) 蛋白會協同作用，負責協助FAK中間協調細胞生長的路徑，或者減少SSEA3聚合時，負責啟動FADD下游細胞凋亡路徑，因此證實SSEA3可以藉由FAK與RIP的結合以調控細胞的命運。
本篇論文發現在乳癌細胞中高度表達的SSEA3與β3GalT5，對於乳癌細胞的惡化侵襲與生長訊息調控之影響，扮演重要角色，因此將可做為未來研發抗癌藥物治療上的應用之基礎方針。

Glycosphingolipids (GSLs) are a type of glycolipids found on cell membrane, some of which are highly or specifically expressed in cancer and therefore can be the targets for therapeutic development. Members of the globo-series GSLs, SSEA3 (Gb5), SSEA4 and Globo-H, are specific GSLs observed in many malignant tissues and correlate with cancer progression. Our studies indicate that these globo-series GSLs can not only serve as markers, but also promote certain signaling pathways associated with tyrosine kinases. In breast cancer, the enzyme β1,3-galactosyltransferase V (β3GalT5) catalyzes the addition of β1,3-linked galactose to Gb4 (GalNAcβ3Galα4Galβ4GlcβCer) to form SSEA3, which serves as the precursor of both SSEA4 (α2,3-sialyl-SSEA3) and Globo-H (α1,2-fucosyl-SSEA3). β3GalT5 is therefore a key enzyme in controlling the expression of these three cancer-related glycolipids. However, the functional roles and regulatory mechanism of β3GalT5 and SSEA3 in breast cancer remain largely unclear.
Here, we show that the expression of β3GalT5 is up-regulated in breast carcinoma and significantly correlates with tumor progression and poor survival in patients with breast cancer. Knockdown of β3GalT5 in breast cancer cells MCF-7 and MDA-MB-231 were found to induce cancer cell apoptosis and inhibit cancer proliferation, and the induced apoptosis was through Fas/FADD-dependent pathway that activated caspase-3 and caspase-8. In addition, lack of β3GalT5 in MDA-MB-231 cells decreased focal adhesion kinase (FAK) expression and its interaction with SSEA3 that suppressed cell migration and adhesion. The co-immunoprecipitation and immunofluorescence results showed that SSEA3, caveolin1 (CAV1), and FAK form a complex on MDA-MB231 cells membrane lipid raft, suggesting that the SSEA3-CAV1-FAK complex contributed to cancer survival. Moreover, we found that the SSEA3 complex is associated with receptor-interacting protein (RIP), a kinase that shuttles between FADD and FAK. We also demonstrated that knockdown of 3GalT5 reduced its association of RIP and increased interaction to FADD that led to cell apoptosis.
Thus, the high expression level of SSEA3 and β3GalT5 in human breast cancer provides a link between tumor progression and survival signaling pathway, and this new finding could be useful for the therapeutic development of breast cancer.

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