Bmi1 represses HLF to drive the formation and development of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent type of primary liver cancer and lacks effective targeted therapy. Previously, we reported that B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1) drives the formation and development of ICC independent of Ink4A/Arf; however, the underlying mechanism remains unclear. Here, we report that hepatic leukaemia factor (HLF) acts as a tumour-suppressor gene in ICC and Bmi1 represses HLF to drive ICC initiation and progression.

RNA sequencing was performed to find the downstream target of Bmi1 in ICC. Bioinformatic analysis and molecular biological techniques were used to examine the expression of Bmi1 and HLF in ICC. Effects of HLF silence or overexpression by lentivirus on cell proliferation or development were evaluated in human ICC cells, xenograft and primary ICC mouse models, respectively. The luciferase reporter assay was used to identify that Bmi1 regulates HLF.

In ICC, HLF expression levels were inversely correlated with Bmi1. Overexpression of HLF inhibited the growth of ICC both in vitro and in vivo, whereas HLF knockout promoted ICC development in ICC mouse models. Importantly, HLF repression reversed the inhibitory effects of Bmi1 knockdown on cell survival, proliferation and colony formation. Luciferase reporter assay results indicated that Bmi1 represses HLF by directly binding to its promoter.

These findings revealed the molecular mechanism through which Bmi1 promotes ICC formation and development and uncovered the role of HLF as a tumour suppressor in ICC.