Cosmc醣類轉換酵素伴隨蛋白在嬰兒血管瘤的角色

Abstract

Cosmc醣類轉換酵素伴隨蛋白在嬰兒血管瘤的角色 嬰兒血管瘤（Infantile Hemangioma）又稱草莓型血管瘤（Strawberry Hemangioma），是兒童常見的良性血管瘤。 血管瘤的特點是嬰兒在1~2個月大時先長成一個小紅點，以後快速的增大到1~1½歲時即停止再長大，而慢慢開始自然消退。故前階段稱增生期，1歲半以後稱消退期。 血管瘤是局部血管內皮細胞的異常增生，文獻上指出異常VEGFR2、TEM8、β1-integrin的聚合物鍵結異常，進一步與VEGFR1競爭生長激素而導致細胞過度增生。 Cosmc 是醣類轉換酵素C1GALT1 特有的chaperone，C1GALT1 可以催化Gal-GalNAc 雙醣的形成(core 1 structure)，進一步催化O-glycan醣化蛋白的形成。Cosmc在血管生成過程中扮演重要角色，在腫瘤生程中也有重要影響，但在血管瘤中的角色不明。 本實驗室的初步結果已發現，相較於退化後血管瘤和其它血管內皮細胞，Cosmc在嬰兒血管瘤的血管內皮細胞有高度過量表現；而上下游的產物（T antigen）也有相對應的改變。另外，造成Cosmc過度表現的血管內皮細胞（HUVEC），它的表現型也有過度增生的現象；這現象的路徑主要來自於磷酸化的Akt和Erk。反過來說，以siRNA降低Cosmc表現的血管內皮細胞的生長是被抑制的。 本實驗進一步研究發現，血管內皮細胞內的第二型血管生成因子接受器（VEGFR2）能夠被Cosmc所修飾，而進一步影響細胞增生；這原因可能來自於Cosmc過度表現的VEGFR2、降解明顯比原來的慢。相反的，以SiRNA降低Cosmc表現的血管內皮細胞，VEGFR2降解是比較快的。這個關於VEGFR2被Cosmc調控的發現，是前所未見的，而且可以解釋Cosmc在血管瘤的角色。

Infantile hemangiomas are localized lesions comprised primarily of aberrant endothelial cells. COSMC plays a crucial role in blood vessel formation and is characterized as a molecular chaperone of T-synthase which catalyzes the synthesis of T antigen (Galβ1,3GalNAc). T antigen expression is associated with tumor malignancy in many cancers. However, roles of COSMC in infantile hemangioma are still unclear. In this study, immunohistochemistry showed that COSMC was upregulated in proliferating hemangiomas compared with involuted hemangiomas. Higher levels of T antigen expression were also observed in the proliferating hemangioma. Overexpression of COSMC significantly enhanced cell growth and phosphorylation of AKT and ERK in human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of COSMC with siRNA inhibited endothelial cell growth. Mechanistic investigation showed that O-glycans were present on VEGFR2 and these structures were modulated by COSMC. Furthermore, VEGFR2 degradation was delayed by COSMC overexpression and facilitated by COSMC knockdown. We also showed that COSMC was able to regulate VEGF-triggered phosphorylation of VEGFR2. Our results suggest that COSMC is a novel regulator for VEGFR2 signaling in endothelial cells and dysregulation of COSMC expression may contribute to the pathogenesis of hemangioma.