黏液蛋白醣化酶 N-acetylegalactosaminyltransferase 1 (GALNT1) 在肝細胞癌扮演之角色

Abstract

肝細胞癌在全球癌症死亡率排名第三位。由於肝細胞癌的惡性行為之特性，在臨床診斷及治療上仍然是一大問題。黏液型醣化修飾作用為蛋白質最常見的轉譯後修飾作用。從過去研究指出，不正常的醣化修飾會參與在癌症發展過程中。GALNT1為黏液型醣化作用步驟中的第一步酵素。但是目前對於GALNT1在肝細胞癌所扮演的角色卻仍然非常不清楚。本研究發現GALNT1在肝細胞癌有高度表現，並且高度表現GALNT1的病人其存活率相較低表現之病人差。從細胞實驗我們發現高表現GALNT1的肝癌細胞可以促進肝癌細胞的惡性行為，例如：細胞遷移和侵襲 ; 反之，降低GALNT1表現則會抑制肝細胞惡性行為。此外，抑制GALNT1表現肝癌細胞會抑制EGF所誘發的細胞遷移和侵襲之惡性行為。並且抑制GALNT1表現可以影響EGFR上的醣化修飾，進而抑制EGFR的磷酸化，進而促進EGFR的降解作用。本研究顯示GALNT1在肝細胞癌中表現量增加，透過抑制GALNT1的表現可以抑制由EGFR所誘發肝癌細胞的惡性行為。未來在肝細胞癌治療研究中，GALNT1是一個具有潛力的方向。

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Management of HCC imposes great challenge due to its malignant characteristics and limited therapeutic drug efficacy. O-glycosylation is a common protein modification, however, aberrant O-glycosylation is associated with many cancer malignancies. GALNT1 is a GalNAc-transferase pivotal in the initiation of protein O-glycosylation, yet, the functional roles of GALNT1 in cancer, particularly HCC, are unknown. In this study we found that GALNT1 is frequently up-regulated in HCC; and higher GALNT1 expression is associated with poorer patient survival. Indeed, overexpression of GALNT1 shows enhanced but knockdown suppressed HCC cell migration and invasion. Further investigation found that knockdown of GALNT1 significantly suppressed EGF-induced HCC cell migration and invasion. Mechanistic investigation shows that knockdown of GALNT1 decreased EGF-triggered EGFR activation and enhanced EGFR degradation by altered O-glycans on EGFR. This study demonstrates that GALNT1 is often overexpressed in HCC and inhibiting GALNT1 expression is sufficient to suppress malignant behaviors of HCC cells by decreasing EGFR signaling suggesting that GALNT1 may be a potential target of therapeutic drug development in the management of HCC.