FXR-Gankyrin axis is involved in development of pediatric liver cancer

Abstract

The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins. We next analyzed FXR-Gank-Tumor suppressor pathways in a large cohort of HBL patients which include 6 controls and 53 HBL samples. Systemic analysis of these samples and RNA-Seq approach revealed that the FXR-Gank axis is activated; markers of hepatic stem cells are dramatically elevated and hepatocyte markers are reduced in HBL samples. In the course of these studies, we found that RNA binding protein CUGBP1 is a new tumor suppressor protein which is reduced in all HBL samples. Therefore, we generated CUGBP1 KO mice and examined HBL signatures in the liver of these mice. Micro-array studies revealed that the HBL-specific molecular signature is developed in livers of CUGBP1 KO mice at very early ages. Thus, we conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma.

C/EBPα‐dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer

“…We next examined molecular alterations in the livers of DEN‐treated S193A mice at 28 weeks post–DEN injections. In WT mice, C/EBPα phosphorylated at S193 is degraded by Gank, which is activated by the reduction of FXR . Therefore, we examined the FXR–Gank pathway in DEN‐treated WT and S193A mice.…”

“…Among 51 HBL samples, we obtained six samples from patients with aggressive HBL that are characterized by very fast growth, by chemoresistance, and by poor postoperative prognosis. These HBL samples have been described in detail …”

PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma

“…We have also analyzed data of RNA-Seq which have been previously published in our paper 14 and are available via NCBI GEO at accession number GSE81928.…”

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

“…CUGBP1 was originally discovered as an important player of myotonic dystrophy and as a regulator of skeletal muscle, heart, and brain functions . However, several reports have shown that CUGBP1 is a key protein that regulates liver biology …”