1. CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma
- Author
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Zhao-Qing Shen, Yi-Fan Chen, Jim-Ray Chen, Yuh-Shan Jou, Pei-Chun Wu, Cheng-Heng Kao, Chih-Hao Wang, Yi-Long Huang, Chian-Feng Chen, Ting-Shuo Huang, Yu-Chiau Shyu, Shih-Feng Tsai, Lung-Sen Kao, and Ting-Fen Tsai
- Subjects
CISD2 ,nonalcoholic fatty liver disease ,hepatocellular carcinoma ,haploinsufficiency ,tumor suppressor gene ,calcium homeostasis ,ER stress ,Serca2b ,Biology (General) ,QH301-705.5 - Abstract
CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca2+ pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca2+ uptake and maintains intracellular Ca2+ homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC.
- Published
- 2017
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