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

Abstract

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.

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

“…The relationship between FOXA2 and tumors has become a research hotspot in recent decades. In line with the findings in hepatocarcinoma, 20 gastric carcinoma, 21 and glioma, 22 the present study experimentally determined that FOXA2 was underexpressed in GBC, suggesting that FOXA2 is potentially linked to the initiation of GBC. Subsequent experiments revealed inverse correlations between FOXA2 expression, TNM stage, and lymph node metastasis, indicating a possible function of FOXA2 in GBC progression.…”

FOXA2 plays a critical role in hepatocellular carcinoma progression and lenvatinib-associated drug resistance

“…McDaniel et al (10) found that FOXA2 regulated the development and differentiation of biliary progenitor cells. Similarly, a previous study by the current authors indicated that downregulation of FOXA2 promoted intrahepatic cholangiocarcinoma development (11). A number of studies have investigated the role of FOXA2 in HCC.…”

“…The current authors previously reported that FOXA2 promotes intrahepatic cholesteatoma by activating the MAPK signaling pathway (11). According to preliminary findings and previous research (11), FOXA2 contributed to tumor progression in HCC cells. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is widely used to treat patients with unresectable HCC.…”

“…FOXA2 regulated tumor behavior by interacting with various genes, including the cadherin 1(CDH1) promoter, forkhead box protein P2 (FOXP2), and staphylococcal nuclease domain containing 1 (SND1) (29,33,34). The current authors previously reported that FOXA2 promotes intrahepatic cholesteatoma by activating the MAPK signaling pathway (11). According to preliminary findings and previous research (11), FOXA2 contributed to tumor progression in HCC cells.…”