title: Inactivation of p27Kip1 promotes chemical mouse liver tumorigenesis in the resistant strain C57BL/6J.
abstract: The biochemical function of p27Kip1 as an inhibitor of cyclin-dependent kinases is well-established, but the role of p27 as a tumor suppressor depends on specific cellular contexts. Previous studies using p27 knockout mice on mixed C57BL/6J x 129/Sv strain background did not find a tumor suppressor role of p27 in the liver. An important feature of mouse liver tumorigenesis is strain-dependent tumor susceptibility. Here, we determined the role of p27 in liver tumorigenesis in C57BL/6J mice, a liver tumor resistant strain, in response to a diethylnitrosamine (DEN) and phenolbarbital (PB) two-stage carcinogenesis protocol. At 6 mo of age, while livers of DEN-PB treated p27+/+ and p27-/- C57BL/6J mice appeared morphologically normal, p27-/- livers, but not p27+/+ livers, contained readily detectable glucose-6-phosphatase (G6Pase)-deficient foci. At the 9-mo time point, p27-/- mice developed significantly enhanced liver tumor phenotypes than p27+/+ mice as demonstrated by increased numbers and sizes of liver surface nodules, increased liver-to-body weight ratios, and increased numbers of G6Pase-deficient nodules and histologically diagnosed foci and adenomas in liver sections. Hepatic lesions in p27-/- livers contained more proliferating hepatocytes than lesions in p27+/+ livers, while the numbers of apoptotic cells appeared similar in lesions of both genotypes. Unexpectedly, tumors in p27-/- livers contained only slightly elevated Cdk2 kinase activity compared with normal livers. These results reveal a liver tumor suppressor role of p27 in this resistant mouse strain, and the need to further study the role of Cdk2 kinase in liver tumor promotion by p27 inactivation.
authors.affiliation: Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center and Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Daqian
authors.initials: D
authors.lastname: Sun
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.forename: Michael
authors.initials: M
authors.lastname: Oertel
authors.forename: Rani S
authors.initials: RS
authors.lastname: Sellers
authors.forename: David A
authors.initials: DA
authors.lastname: Shafritz
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D017931:DNA Primers; D004195:Disease Models, Animal; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007150:Immunohistochemistry; D007700:Kinetics; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: C493961:Cdkn1b protein, mouse; D017931:DNA Primers; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005952:Glucose-6-Phosphatase