摘要
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. Shen et al. demonstrate that CISD2 is a haploinsufficient 4q tumor suppressor in liver. Cisd2 haploinsufficiency causes nonalcoholic fatty liver disease and promotes hepatocellular carcinoma (HCC). Conversely, increase of Cisd2 suppresses HBV-associated and carcinogen-induced HCC. CISD2 may be a molecular target for HCC prevention.
原文 | English |
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頁(從 - 到) | 2198-2211 |
頁數 | 14 |
期刊 | Cell Reports |
卷 | 21 |
發行號 | 8 |
DOIs | |
出版狀態 | Published - 21 11月 2017 |