Difference in driver gene expression patterns between perihilar and peripheral intrahepatic cholangiocarcinoma in an experimental mouse model

Background The prognosis of intrahepatic cholangiocarcinoma (ICC) is based on tumor localization; however, the mechanism remains unknown. Therefore, we investigated the biological characteristics of perihilar and peripheral ICC in a mouse model. Methods The model was established by the administration of three oncogenic plasmids harboring myristoylated AKT, mutated human YAP, and pCMV‐Sleeping Beauty into the mice. The perihilar and peripheral ICC tumors that developed in the same mouse were assessed for the expression of cell adhesion factors and driver genes with immunohistochemistry and reverse transcription polymerase chain reaction (RT‐PCR). Results The perihilar ICC tumors were irregularly shaped, whereas the peripheral tumors were mostly circular, similar to the differences found in patients. Alpha‐smooth muscle actin was strongly expressed in the perihilar tumors at 10 weeks, and vimentin expression was significantly up‐regulated in the perihilar ICC at 14 weeks. Fgfr2 level significantly increased in peripheral ICC at 10 weeks, whereas Idh2 expression was up‐regulated in perihilar ICC. Conclusions Despite diffuse injection of oncogenic plasmid, expression of driver genes and oncogenes in ICC tumor cells differs depending on the tumor localization, resulting in changes in epithelial‐mesenchymal transition, which may explain the different outcomes of patients with peripheral and perihilar ICC. Highlight Adachi and colleagues investigated differences between the perihilar and peripheral tumor locations of intrahepatic cholangiocarcinoma (ICC) in an experimental mouse model. There were no significant differences in epithelial‐mesenchymal transition‐related proteins, but driver gene expression levels of Fgfr2 significantly increased in peripheral ICC, whereas Idh2 expression was up‐regulated in perihilar ICC.