PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1.

Abstract

BACKGROUND:

Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis.

METHODS:

HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis.

RESULTS:

Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development.

CONCLUSIONS:

This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.

• Authors: Fuqiang Huang, Jing Guo, Na Zhao, Mengjie Hou, Xiaochen Gai, Shuhui Yang, Pei Cai, Yanan Wang, Qian Ma, Qi Zhao, Li Li, Huayu Yang, Yanling Jing, Di Jin, Zhongdong Hu, Xiaojun Zha, Hongyang Wang, Yilei Mao, Fangming Liu, Hongbing Zhang
• Journal: Journal of translational medicine (J Transl Med) Vol. 22 Issue 1 Pg. 254 (Mar 08 2024) ISSN: 1479-5876 [Electronic] England
• PMID: 38459588 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s).

Chemical References

• GOLM1 protein, human
• Membrane Proteins
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Humans
• Mice
• Carcinoma, Hepatocellular (pathology)
• Fibrosis
• Hepatitis B (complications)
• Hepatitis B virus
• Inflammation (pathology)
• Liver (pathology)
• Liver Neoplasms (pathology)
• Membrane Proteins (metabolism)
• Mice, Knockout
• PTEN Phosphohydrolase (metabolism)