Role of Hepatocyte Nuclear Factor 4α in Regulating Hepatic Differentiation and the Inflammatory Response in HCC

Abstract

HNF4 is a nuclear hormone receptor protein mostly expressed in the liver but also expressed at lower levels in the gut, kidney, and pancreatic beta cells. Three different isoforms have been identified, HNF 4α, HNF 4β and HNF 4γ. The structure of HNF 4α protein has two transactivation Abstract: Limited treatment options are available for hepatocellular carcinoma (HCC), especially in the advanced stage, which is associated with a poor prognosis. Many studies have demonstrated that hepatocyte nuclear factor 4α (HNF 4α) plays an important role in hepatic differentiation and the carcinogenesis of HCC. HNF 4α critically regulates hepatic differentiation by controlling a large number of genes involved in hepatic functions including metabolism, xenobiotic detoxification, bile acid synthesis, and serum protein production. It has also been confirmed to play an important role in the inflammatory environment in HCC. Thus, HNF 4α is considered to be a promising target for the treatment of HCC. Some studies have demonstrated that regulating HNF 4α expression in HCC had beneficial effects in in vivo and in vitro experiments. We herein review the role of HNF 4α in regulating hepatic metabolism and the inflammatory response, aiming to provide some ideas on induced hepatic differentiation therapy and regulating the inflammatory microenvironment for the treatment of advanced HCC.

Hepatogenesis and hepatocarcinogenesis: Alignment of the main signaling pathways

“…Forced re‐expression of HNF4α in dedifferentiated hepatoma cell lines is sufficient to induce upregulation of a set of hepatocytic and epithelial marker genes, including CYP3A4 , ALB , and CDH1 . This could improve hepatic functions like urea production and glycogen storage and decrease the percentage of CD133 + and CD90 + cells (C. Yin et al, 2008; Hang et al, 2017; W. L. Zhou et al, 2019). Similarly, forced overexpression of HNF1α induced hepatoma cells differentiation into mature hepatocytes by restoring miR‐192, miR‐194, and p21 levels and causing G2/M cell cycle arrest (Zeng et al, 2011).…”