Liver‐specific DICER1 syndrome model mice develop cystic liver tumors with defective primary cilia

• Published in: The Journal of pathology Vol. 264; no. 1; pp. 17 - 29
• Main Authors: Oikawa, Keiki, Ohno, Shin‐ichiro, Ono, Kana, Hirao, Kaito, Murakami, Ayano, Harada, Yuichirou, Kumagai, Katsuyoshi, Sudo, Katsuko, Takanashi, Masakatsu, Ishikawa, Akio, Mineo, Shouichirou, Fujita, Koji, Umezu, Tomohiro, Watanabe, Noriko, Murakami, Yoshiki, Ogawa, Shinichiro, Schultz, Kris Ann, Kuroda, Masahiko
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.09.2024; Wiley Subscription Services, Inc
• Subjects: Animal models; Animals; Bile ducts; Bile Ducts - pathology; Cholangiocarcinoma; Cilia; Cilia - metabolism; Cilia - pathology; cystic liver; DEAD-box RNA Helicases - deficiency; DEAD-box RNA Helicases - genetics; DICER1 syndrome; Disease Models, Animal; Epithelium; Fibrosis; Hepatocellular carcinoma; Hyperplasia; intrahepatic cholangiocarcinoma; Liver; Liver - metabolism; Liver - pathology; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Mice; microRNA; Molecular modelling; mouse model; Mutation; primary cilia; Ribonuclease III - genetics; Ribonuclease III - metabolism; Tumorigenesis; Tumors; mouse model; primary cilia; cystic liver; microRNA; DICER1 syndrome; hepatocellular carcinoma; intrahepatic cholangiocarcinoma
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.6320

DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver‐specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.