Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
Biosci Biotechnol Biochem. 2021 Oct 21;85(11):2263-2273. doi: 10.1093/bbb/zbab156.
The upregulation of anterior gradient 2 (AGR2) has been observed in cholangiocarcinoma (CCA) cells, nras-mutant zebrafish, and specimens derived from CCA patients. Our previous study reported AGR2 splicing into AGR2vH to facilitate CCA cell aggressiveness, while this work aims to investigate the molecular mechanisms underlying AGR2vH. First, AGR2vH upregulation was demonstrated in CCA tissues derived from patients. For in vitro studies, established AGR2vH-overexpressing KKU-213A cells were found to exhibit increased proliferation and clonogenicity. In vivo tumorigenicity assessed in a mouse model represented higher tumorigenic potential in AGR2vH-overexpressing cell xenograft mice. Next, LC-MS/MS was analyzed, indicating that AGR2vH may be associated with CCA cell proliferation via Wnt/β-catenin signaling pathway activation, which was verified by β-catenin expression and nuclear translocation. The current results provide evidence that AGR2vH upregulation promotes tumorigenicity in CCA cells linked with an alteration of CCA cell proteome.
AGR2 的上调已在胆管癌 (CCA) 细胞、NRAS 突变的斑马鱼和 CCA 患者标本中观察到。我们之前的研究报告称 AGR2 剪接成 AGR2vH 以促进 CCA 细胞侵袭性，而这项工作旨在研究 AGR2vH 的分子机制。首先，在源自患者的 CCA 组织中证明了 AGR2vH 的上调。对于体外研究，发现表达 AGR2vH 的 KKU-213A 细胞表现出增殖和集落形成能力增强。在小鼠模型中的体内致瘤性评估中，AGR2vH 过表达细胞异种移植小鼠的致瘤潜能更高。接下来，通过 LC-MS/MS 分析表明，AGR2vH 可能通过 Wnt/β-catenin 信号通路的激活与 CCA 细胞增殖有关，这通过β-catenin 的表达和核易位得到验证。目前的结果提供了证据，表明 AGR2vH 的上调促进了与 CCA 细胞蛋白质组改变相关的 CCA 细胞的致瘤性。
