Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, with complex pathogenesis and poor clinical prognosis. It was shown that hepatocyte nuclear factor 1β (HNF1B) is strongly expressed in hepatocyte and involved in liver development. Relevant studies have shown that HNF1B can be used as a marker for the identification of hepatocellular cholangiocarcinoma. However, regarding the mechanism by which HNF1B regulates the behavior of cancer cells to influence the development, malignancy and metastasis ability of HCC, is poorly understood at present.

In this study, the proliferation, migration, invasion, and apoptosis of liver cancer cells was investigated by modulating the expression of HNF1B in HCC cells. Furthermore, bioinformatics analysis: including differential gene and survival analysis, clinical relevance, GO/KEGG enrichment, immune cell infiltration, gene pathway prediction and PPI network analysis were applied to explore the mechanism of HNF1B to influence the development, malignancy and metastasis of HCC.

Our results indicated that over-expression of HNF1B promoted the proliferation (*P < 0.05), migration (***P < 0.001) and invasive (**P < 0.01) ability of HCC cells, while significantly inhibited apoptosis. Importantly, overexpression of HNF1B may be associated with the transformation process from hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (ICC) (****P < 0.0001). Bioinformatics analysis showed that HNF1B increased tumor cell heterogeneity by remodeling in the tumor microenvironment including immune cell infiltration, cell adhesion, and extracellular matrix. Moreover, HNF1B regulates the transformation of HCC to ICC through Notch, Hippo and neuroactive ligand-receptor interaction signaling pathways.

Our study elucidated the functional roles of HNF1B on regulating the biological behavior of HCC cells, suggesting that HNF1B could be an important molecular marker of HCC. This finding provides a potential molecular target for the diagnosis and prognosis of HCC.