Promyelocytic leukemia protein deficiency leads to spontaneous formation of liver tumors in hepatitis C virus transgenic mice

Abstract

Persistent infection with hepatitis C virus (HCV) is a known risk factor for the development of hepatocellular carcinoma (HCC). The lack of the tumor suppressor promyelocytic leukemia protein (PML) in combination with HCV fosters hepatocarcinogenesis via induction of HCC using diethylnitrosamine (DEN) in a rodent model. However, the spontaneous development of malignant lesions in PML‐deficient mice with an HCV‐transgene (HCV tg ) has not been investigated thus far. We crossed PML‐deficient mice with HCV transgene expressing mice and observed the animals for a period of 12 months. Livers were examined macroscopically and histologically. Gene expression analysis was performed on these samples, and compared with expression of selected genes in human samples of patients undergoing liver transplantation for HCC. In vitro studies were performed in order to analyze the selected pathways. Genetic depletion of PML in combination with HCV tg coincided with an increased hepatocyte proliferation, resulting in development of HCCs in 40% of the PML‐deficient livers. No tumor development was observed in mice with either the PML‐knockout (PML −/− ) or HCV tg alone. Gene expression profiling uncovered pathways involved in cell proliferation, such as NLRP12 and RASFF6. These findings were verified in samples from human livers of patients undergoing liver transplantation for HCC. Further in vitro studies confirmed that lack of PML, NLRP12, and RASFF6 leads to increased cell proliferation. The lack of PML in combination with HCV is associated with increased cell proliferation, fostering tumor development in the liver. Our data demonstrate that PML acts as an important tumor suppressor in HCV‐dependent liver pathology.

TRIM proteins in hepatocellular carcinoma

“…PML declines in HCV transgenic mice and develops more spontaneous or phenobarbital/diethylnitrosamine (DEN) induced HCC via down-regulating RNA NLRP12, Ras association domain-containing protein 6 (RASSF6), and TRAIL expressions [ 133 – 135 ]. HCV core protein interacts and inactivates PML-IV in PML-NBs to inhibit phosphorylation and acetylation of P53, which leads to dysregulation of Fas in HCC [ 91 , 136 ].…”

Interplay between RNA Viruses and Promyelocytic Leukemia Nuclear Bodies

“…PML deficiency in HCV-transgenic (HCV tg ) PML-deficient (PML −/− ) mice enhanced susceptibility to tumor induction by diethylnitrosamine (DEN)/phenobarbital (PB) treatment compared to WT, HCV tg , and PML −/− mice groups by enhancing hepatocyte proliferation [ 38 ]. In the absence of DEN/PB induction, 40% of HCV tg PML −/− mice maintained for long-term duration also formed spontaneous tumors with greater hepatocyte proliferation, whereas no liver lesions were observed among the other groups [ 69 ]. A significant downregulation of PML and NFκB target genes associated with tumor suppressive functions ( RASSF6, NLRP12) was observed in HCV tg PML −/− mice [ 69 ].…”

“…In the absence of DEN/PB induction, 40% of HCV tg PML −/− mice maintained for long-term duration also formed spontaneous tumors with greater hepatocyte proliferation, whereas no liver lesions were observed among the other groups [ 69 ]. A significant downregulation of PML and NFκB target genes associated with tumor suppressive functions ( RASSF6, NLRP12) was observed in HCV tg PML −/− mice [ 69 ]. These mechanisms highlight the potential tumor-suppressive functions of PML in HCV-associated carcinogenesis.…”