Arid1a mutation suppresses TGF-β signaling and induces cholangiocarcinoma.

ABSTRACT: Activating KRAS mutations and functional loss of members of the SWI/SNF complex, including ARID1A, are found together in the primary liver tumor cholangiocarcinoma (CC). How these mutations cooperate to promote CC has not been established. Using murine models of hepatocyte and biliary-specific lineage tracing, we show that Kras and Arid1a mutations drive the formation of CC and tumor precursors from the biliary compartment, which are accelerated by liver inflammation. Using cultured cells, we find that Arid1a loss causes cellular proliferation, escape from cell-cycle control, senescence, and widespread changes in chromatin structure. Notably, we show that the biliary proliferative response elicited by Kras/Arid1a cooperation and tissue injury in CC is caused by failed engagement of the TGF

SUBMITTER: Guo B 

PROVIDER: S-EPMC9808599 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature