Shen Junyi, Zhou Yongjie, Zhang Xiaoyun, Peng Wei, Peng Chihan, Zhou Qiang, Li Chuan, Wen Tianfu, Shi Yujun
Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Chengdu, China.
Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, MCH, West China Hospital, Sichuan University, Chengdu, China.
Aging (Albany NY). 2019 Nov 5;11(21):9280-9294. doi: 10.18632/aging.102332.
Intrahepatic cholangiocarcinoma (ICC) is characterized by a highly aggressive nature and a dismal outcome. FOXA2 is an archetypal transcription factor involved in cholangiocyte proliferation.
FOXA2 expression was negatively correlated with tumor stage (p = 0.024). Univariate and multivariate analyses showed that low FoxA2 expression was associated with tumor relapse and survival. At 20 weeks after TAA administration, FoxA2 mice displayed significant manifestations of neoplasia, while WT mice did not.RNA sequencing analysis showed that the expression of genes in the MAPK signaling pathway was significantly higher in FoxA2 mice. IHC and Western blot results showed that p-ERK1/2, CREB1 and RAS were highly expressed in FoxA2 mice. Furthermore, using in vitro experiments with siRNA, we found that low expression of FoxA2 could exacerbate the metastatic potential of ICC. The expression of p-ERK1/2 and RAS, which are key mediators of the MAPK signaling pathway, was significantly increased.
Low FOXA2 expression negatively affected the prognosis of patients with ICC. Loss of FoxA2 expression could promote intrahepatic bile duct neoplasia partly via activation of the MAPK signaling pathway.
In all, the data of 85 patients with ICC were retrospectively collected and analyzed. TAA was used to induce ICC in FoxA2 mice and WT mice. RNA-sequencing analysis was used to identify the expression of different genes.
肝内胆管癌（ICC）具有高度侵袭性且预后不良。FOXA2是一种参与胆管细胞增殖的典型转录因子。
FOXA2表达与肿瘤分期呈负相关（p = 0.024）。单因素和多因素分析表明，低FoxA2表达与肿瘤复发和生存相关。在给予TAA后20周，FoxA2小鼠出现明显的肿瘤形成表现，而野生型小鼠未出现。RNA测序分析表明，FoxA2小鼠中MAPK信号通路中的基因表达显著更高。免疫组化和蛋白质印迹结果表明，p-ERK1/2、CREB1和RAS在FoxA2小鼠中高表达。此外，通过使用siRNA进行体外实验，我们发现FoxA2低表达可加剧ICC的转移潜能。MAPK信号通路的关键介质p-ERK1/2和RAS的表达显著增加。
低FOXA2表达对ICC患者的预后产生负面影响。FoxA2表达缺失可能部分通过激活MAPK信号通路促进肝内胆管肿瘤形成。
总共回顾性收集并分析了85例ICC患者的数据。使用TAA在FoxA2小鼠和野生型小鼠中诱导ICC。使用RNA测序分析来鉴定不同基因的表达。
