Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Mutations in the tumor suppressor Folliculin (FLCN) gene cause Birt-Hogg-Dube' (BHD) syndrome, linked to various tumors.
• FLCN loss dysregulates cellular pathways, including mTORC1, TFEB, and TFE3, promoting tumorigenesis.
• Previous studies indicated FLCN-deficient mice are protected from liver damage, but its role in liver cancer was unknown.

Purpose of the Study:

• To investigate the role of hepatic Folliculin (FLCN) loss in liver carcinogenesis.
• To elucidate the molecular mechanisms driving FLCN-loss-associated liver cancer.

Main Methods:

• Generation of Flcn liver-specific conditional knockout (Flcn^LiKO) mice.
• Induction of liver tumors using diethylnitrosamine (DEN) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).
• Analysis of tumor development, histological features, and molecular signaling pathways, including TFE3, TFEB, and mTORC1.

Main Results:

• Hepatic FLCN loss in aged Flcn^LiKO mice leads to spontaneous liver cancer with inflammation, fibrosis, and cholangiocarcinoma features, predominantly in males.
• Flcn^LiKO mice exhibit increased susceptibility to DEN- or DDC-induced liver tumors.
• Depletion of TFE3, not TFEB, in Flcn^LiKO mice livers fully rescued the cancer phenotype and normalized mTORC1 signaling.

Conclusions:

• Hepatic loss of FLCN promotes liver carcinogenesis, characterized by inflammation, fibrosis, and cholangiocarcinoma.
• TFE3 is identified as the primary driver of liver cancer and mTORC1 hyperactivity in FLCN-deficient conditions.
• Targeting TFE3 may offer a therapeutic strategy for FLCN-related liver cancers.