Transcription coactivator PBP/MED1-deficient hepatocytes are not susceptible to diethylnitrosamine-induced hepatocarcinogenesis in the mouse.
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/MED1(DeltaLiv)) mice, we reported that PBP/MED1 is essential for liver regeneration and the peroxisome proliferator-activated receptor alpha 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/MED1(DeltaLiv) 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/MED1(DeltaLiv) mouse livers. Multiple hepatocellular carcinomas (HCCs) developed in the DEN-initiated PBP/MED1(fl/fl) and PBP/MED1(DeltaLiv) mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1(DeltaLiv) 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/MED1(DeltaLiv) mouse livers were transplantable in athymic nude mice and these maintained PBP/MED1(fl/fl) genotype. PBP/MED1(fl/fl) HCC cell line derived from these tumors expressed PBP/MED1 and deletion of PBP/MED1(fl/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.
Matsumoto
Kojiro
K
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Huang
Jiansheng
J
Viswakarma
Navin
N
Bai
Liang
L
Jia
Yuzhi
Y
Zhu
Yiwei Tony
YT
Yang
Gongshe
G
Borensztajn
Jayme
J
Rao
M Sambasiva
MS
Zhu
Yi-Jun
YJ
Reddy
Janardan K
JK
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D003114:Colony-Forming Units Assay; D004052:Diethylnitrosamine / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects*; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D056913:Mediator Complex Subunit 1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude
D000477:Alkylating Agents; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D004052:Diethylnitrosamine