Transcription coactivator PBP/MED1-deficient hepatocytes are not susceptible to diethylnitrosamine-induced hepatocarcinogenesis in the mouse

Abstract

Nuclear receptor coactivator [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] is a critical component of the mediator transcription complex. Disruption of this gene in the mouse results in embryonic lethality. Using the PBP/MED1 liver conditional null (PBP/MED1ΔLiv) mice, we reported that PBP/MED1 is essential for liver regeneration and the peroxisome proliferator-activated receptor α ligand Wy-14,643-induced receptor-mediated hepatocarcinogenesis. We now examined the role of PBP/MED1 in genotoxic chemical carcinogen diethylnitrosamine (DEN)-induced and phenobarbital-promoted hepatocarcinogenesis. The carcinogenic process was initiated by a single intraperitoneal injection of DEN at 14 days of age and initiated cells were promoted with phenobarbital (PB) (0.05%) in drinking water. PBP/MED1ΔLiv mice, killed at 1, 4 and 12 weeks, revealed a striking proliferative response of few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1ΔLiv mouse livers. Multiple hepatocellular carcinomas (HCCs) developed in the DEN-initiated PBP/MED1fl/fl and PBP/MED1ΔLiv mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1ΔLiv mice were PBP/MED1 positive. None of the tumors was PBP/MED1 negative implying that hepatocytes deficient in PBP/MED1 are not susceptible to neoplastic conversion. HCC that developed in PBP/MED1ΔLiv mouse livers were transplantable in athymic nude mice and these maintained PBP/MED1fl/fl genotype. PBP/MED1fl/fl HCC cell line derived from these tumors expressed PBP/MED1 and deletion of PBP/MED1fl/fl allele by adeno-Cre injection into tumors caused necrosis of tumor cells. These results indicate that PBP/MED1 is essential for the development of HCC in the mouse.

Fabrication, optimization, and characterization of umbelliferone β-D-galactopyranoside-loaded PLGA nanoparticles in treatment of hepatocellular carcinoma: in vitro and in vivo studies

“…[24][25][26][27][28] Histological studies reveal that the HCC expansion occurs in the backdrop of chronic inflammation and NF-κB is the chief mediator of inflammation, regulating other inflammatory molecules either downstream or upstream. 18,23,29 Liver is the production center for synthesis of cytokines such as TNF-α, IL-1β, and IL-6 by blood cells (monocytes and lymphocytes). Not only liver but also few other cells such as murine, kupffer cells, and human hepatocytes produce IL-1β, IL-6, and TNF-α.…”

The Electronics of HER2/neu Positive Breast Cancer Cells

“…All tumors that arise in mice carrying a conditional liver PBP knockout develop from cells that have retained PBP expression. This indicates that PBP is required for the development of hepatocellular carcinoma in mice (Matsumoto et al 2010). Moreover, it has been shown that PBP is required for mammary gland development (Yuzhi Jia et al 2005).…”

Chemical Carcinogenesis and Nasopharyngeal Carcinoma

“…No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1DLiv mouse livers. Multiple hepatocellular carcinomas developed in the DEN-initiated PBP/MED1fl/fl and PBP/MED1DLiv mice [67]. DEN may activate PDGFR /PIK3CA/Akt signaling through -Catenin, and mediate C/EBP phosphorylation through the ubiquitin-proteasome system (UPS), and regulate PBP/MED1, and involve nasopharyngeal carcinogenesis.…”