黏液蛋白醣化酵素GALNT2經由修飾MET受體 調控胃癌的惡性程度

Abstract

異常的醣化作用影響癌細胞的惡性度。乙烯半乳糖胺轉移酶(N-acetylgalactosaminyltransferase 2, GALNT2)屬於黏液型醣基酵素，作用於醣化反應的起始步驟。本研究發現GALNT2 透過修飾肝細胞生長因子接受器(HGFR，又稱MET)，能夠抑制胃腺癌(GCA)的惡性程度。胃腺癌組織中mRNA 與protein 的GALNT2表現比正常的胃腺組織少， 發現GALNT2的表現量與胃癌病患的惡性度有關， GALNT2表現較少的病患其存活率較低。抑制胃癌細胞株GALNT2的表現，會增加胃癌細胞的惡性度；包括提升癌細胞的生長、轉移和侵襲行為。相反的，提高胃癌細胞GALNT2的表現時，胃癌細胞的惡性度降低。動物實驗發現，輸注GLANT2表現受抑制的胃癌細胞株,會增加胃癌細胞在裸鼠體內的轉移。在訊息傳遞的研究中發現，抑制胃癌細胞GALNT2的表現會改變MET 上的醣基構造，也會促進MET 的磷酸化。增加細胞內GALNT2的表現時MET 的磷酸化則減少。添加MET抑制劑，PHA665752，會抑制GALNT2 引起的GCA 惡性行為，顯示GALNT2影響GCA的惡性程度是經由修飾MET引起的。本研究發現GALNT2 的表現與胃腺癌惡性行為有關。提高GALNT2的表現可抑制胃腺癌細胞惡性度，提供MET上O-醣基化的改變對MET活性的影響和胃腺癌發展的重要見解。 關鍵字: 乙烯半乳糖胺轉移酶, O-醣基化, 肝細胞生長因子接受器, 胃腺癌

Aberrant glycosylation determines the malignant characters of cancers. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), an enzyme that mediates the initial step of mucin type-O glycosylation, suppresses malignant phenotypes in gastric adenocarcinoma (GCA) by modifying the activity of the MET (Hepatocyte growth factor receptor). GALNT2 mRNA and protein were downregulated in GCAs, and these events were associated with more advanced disease and shorter recurrence-free survival. Suppressing GALNT2 expression in GCA cells increased cell growth, migration, and invasion in vitro, and tumor metastasis in vivo. Mechanistic investigations revealed that GALNT2 knockdown enhanced phosphorylation of MET and overexpression of GALNT2 decreased MET phospohrylation. We also revealed that GALNT2 effected the Tn antigen on MET. Inhibiting MET activity with PHA665752 decreased the malignant phenotypes caused by GALNT2 knockdown in GCA cells, establishing the important role of MET in the effects mediated by GALNT2. Our results indicate that GALNT2 suppresses the malignant potential of GCA cells and provide novel insights into the significance of O-glycosylation in MET activity and GCA progression. Keywords: GALNT2, N-acetylgalactosaminyltransferase, O-glycosylation, Hepatocyte growth factor, Receptor tyrosine kinase, gastric adenocarcinoma (GCA)