Research Paper Volume 11, Issue 21 pp 9280—9294

Loss of FoxA2 accelerates neoplastic changes in the intrahepatic bile duct partly via the MAPK signaling pathway

Junyi Shen 1, , Yongjie Zhou 2, , Xiaoyun Zhang 1, , Wei Peng 1, , Chihan Peng 1, , Qiang Zhou 1, , Chuan Li 1, , Tianfu Wen 1, , Yujun Shi 2, ,

  • 1 Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Chengdu, China
  • 2 Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, MCH, West China Hospital, Sichuan University, Chengdu, China

received: July 27, 2019 ; accepted: September 22, 2019 ; published: November 5, 2019 ;
How to Cite

Copyright © 2019 Shen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Intrahepatic cholangiocarcinoma (ICC) is characterized by a highly aggressive nature and a dismal outcome. FOXA2 is an archetypal transcription factor involved in cholangiocyte proliferation.

Results: 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.

Conclusion: 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.

Materials and methods: 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.


ICC: Intrahepatic cholangiocarcinoma; FOXA2: Forkhead box transcription factor A2; MMP-9: metalloproteinase-9; TIBL: total bilirubin; ALB: albumin; ALT: alanine aminotransferase; ALP: alkaline phosphatase; TAA: Thioacetamide; OS: Overall survival; RFS: Recurrence-free survival; MVI: Microvascular invasion; HBsAg: hepatitis B virus surface antigen; CA19-9: Carbohydrate antigen 19.