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

Kojiro Matsumoto, Jiansheng Huang, Navin Viswakarma, Liang Bai, Yuzhi Jia, Yiwei Tony Zhu, Gongshe Yang, Jayme Borensztajn, M. Sambasiva Rao, Yi Jun Zhu, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

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 phenobarbitalpromoted 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/MED1γLiv mice, killed at 1, 4 and 12 weeks, revealed a striking proliferative response of few residual PBP/MED1-positive hepatocytes that escaped Cremediated 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/MED1γLiv mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1γLiv 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/MED1γLiv 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.

Original languageEnglish (US)
Pages (from-to)318-325
Number of pages8
JournalCarcinogenesis
Volume31
Issue number2
DOIs
Publication statusPublished - Feb 1 2010

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ASJC Scopus subject areas

  • Cancer Research

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