Custode Bruno Maria, Annunziata Francesco, Dos Santos Matos Felipe, Schiano Valentina, Maffia Veronica, Lillo Milena, Colonna Rita, De Cegli Rossella, Ballabio Andrea, Pastore Nunzia
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (NA), Italy.
Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.
Cell Death Differ. 2025 Apr 6. doi: 10.1038/s41418-025-01486-8.
Mutations in the tumor suppressor gene Folliculin (FLCN) are responsible for Birt-Hogg-Dube' (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis. While previous studies showed that Flcn liver-specific conditional knockout (Flcn) mice are protected from developing liver fibrosis and damage upon high-fat diet exposure, the potential role of FLCN loss in liver carcinogenesis remained unexplored. Here, we demonstrate that hepatic loss of FLCN in mice results in cancer associated with inflammation and fibrosis with features of cholangiocarcinoma (CCA). This phenotype emerges in mice over 90-week-old, with a male predominance. Moreover, Flcn mice are more prone to develop diethylnitrosamine (DEN)- or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced liver tumors with heterogenous histological features. Notably, depletion of TFE3, but not TFEB, in the liver of Flcn mice fully rescues the cancer phenotype and normalized mTORC1 signaling, highlighting TFE3 as the primary driver of liver cancer and mTORC1 hyperactivity in the absence of FLCN.
肿瘤抑制基因卵泡抑素（FLCN）的突变是导致Birt-Hogg-Dube综合征（BHD）的原因，这是一种罕见的遗传性疾病，使受影响的个体易患皮肤肿瘤、肺囊肿和肾肿瘤。FLCN调节关键的细胞通路，包括TFEB、TFE3和mTORC1，这些通路对于维持细胞内稳态至关重要。FLCN的缺失导致mTORC1的过度激活以及TFEB和TFE3的组成性激活，从而促进肿瘤发生。虽然先前的研究表明，肝脏特异性条件性敲除Flcn（Flcn）小鼠在高脂饮食暴露下可免受肝纤维化和损伤的影响，但FLCN缺失在肝癌发生中的潜在作用仍未得到探索。在这里，我们证明小鼠肝脏中FLCN的缺失会导致与炎症和纤维化相关的癌症，并具有胆管癌（CCA）的特征。这种表型出现在90周龄以上的小鼠中，以雄性为主。此外，Flcn小鼠更容易发生二乙基亚硝胺（DEN）或3,5-二乙氧基羰基-1,4-二氢可力丁（DDC）诱导的具有异质性组织学特征的肝肿瘤。值得注意的是，在Flcn小鼠肝脏中耗尽TFE3而非TFEB可完全挽救癌症表型并使mTORC1信号正常化，这突出了TFE3是在缺乏FLCN时肝癌和mTORC1过度活跃的主要驱动因素。
