Hepatic factor MANF drives hepatocytes reprogramming by detaining cytosolic CK19 in intrahepatic cholangiocarcinoma.

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is characterized by poor prognosis and limited treatment. Hepatocytes have been considered as one of the origins of ICC, however, the underlying mechanisms remain unclear. Here, we found mesencephalic astrocyte-derived neurotrophic factor (MANF), a hepatoprotective factor, was exceptionally upregulated in human ICC tissues and experimental mouse ICC models induced by sleeping beauty transposon (SBT) or thioacetamide (TAA) challenge. We identified MANF as a biomarker for distinguishing the primary liver cancer and verified the oncogenic role of MANF in ICC using cell lines overexpressing/knocked down MANF and mice specifically knocked in/out MANF in hepatocytes. Lineage tracing revealed that MANF promoted mature hepatocyte transformation into ICC cells.

SUBMITTER: Mei Q 

PROVIDER: S-EPMC12325741 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature