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.

中文翻译：

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AGR2vH（一种致癌的 AGR2 剪接转录本）的过度表达会增强胆管癌细胞的致瘤性和蛋白质组改变。


在胆管癌 (CCA) 细胞、nras 突变斑马鱼和来自 CCA 患者的标本中观察到前梯度 2 (AGR2) 的上调。我们之前的研究报道了AGR2剪接至AGR2vH以促进CCA细胞的侵袭性，而本工作旨在研究AGR2vH背后的分子机制。首先，AGR2vH 在源自患者的 CCA 组织中得到上调。对于体外研究，发现已建立的 AGR2vH 过表达 KKU-213A 细胞表现出增殖和克隆形成增加。在小鼠模型中评估的体内致瘤性表明，AGR2vH 过表达细胞异种移植小鼠具有更高的致瘤潜力。接下来，LC-MS/MS分析表明AGR2vH可能通过Wnt/β-catenin信号通路激活与CCA细胞增殖相关，并通过β-catenin表达和核转位验证了这一点。目前的结果提供证据表明，AGR2vH 上调可促进 CCA 细胞的致瘤性，并与 CCA 细胞蛋白质组的改变有关。