近日，美国冷泉港实验室David A. Tuveson研究组发现，聚糖CA19-9参与促进小鼠胰腺炎和胰腺癌发生。这一研究成果发表在2019年6月21日出版的国际著名学术期刊《科学》上。
为了研究聚糖在胰腺疾病中的作用，研究人员在小鼠中诱导表达了人岩藻糖基转移酶3和β1,3-半乳糖苷转移酶5，从而产生了一种聚糖（sialyl-Lewis），这又被称为碳水化合物抗原19-9（CA19-9）。值得注意的是，CA19-9的表达使得小鼠产生了快速且严重的胰腺炎，并伴随表皮生长因子受体（EGFR）信号通路的过度激活。分子机制表明，CA19-9对基质细胞蛋白fibulin-3的修饰增强了其与EGFR的相互作用，因此，阻断fibulin-3、EEFR配体或CA19-9均能够在类器官体中抑制EGFR的过激活。CA19-9引起的胰腺炎是可逆的，并能够被CA19-9的抗体所抑制。CA19-9也能够与癌基因KrasG12D来产生恶性胰腺癌。这些发现提示，CA19-9在胰腺炎和胰腺癌发生过程中有作用，并且能够作为疾病治疗靶点。
据悉糖基化的改变能够表征组织炎症和肿瘤生成，但是这些改变是否参与疾病的发生还了解甚少。
附：英文原文
Title: The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice
Author: Dannielle D. Engle, Hervé Tiriac, Keith D. Rivera, Arnaud Pommier, Sean Whalen, Tobiloba E. Oni, Brinda Alagesan, Eun Jung Lee, Melissa A. Yao, Matthew S. Lucito, Benjamin Spielman, Brandon Da Silva, Christina Schoepfer, Kevin Wright, Brianna Creighton, Lauren Afinowicz, Kenneth H. Yu, Robert Grützmann, Daniela Aust, Phyllis A. Gimotty, Katherine S. Pollard, Ralph H. Hruban, Michael G. Goggins, Christian Pilarsky, Youngkyu Park, Darryl J. Pappin, Michael A. Hollingsworth, David A. Tuveson
Issue&Volume:Vol 364, Issue 6446,21 June 2019
Abstract: Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9–mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.
DOI: 10.1126/science.aaw3145
Source:https://science.sciencemag.org/content/364/6446/1156