Loss of p27Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation.
Effects of p27Kip1 inactivation on tumorigenesis vary from promotion to prevention dependent on the mouse models used. When p27 inactivation has a positive effect on tumorigenesis, de-regulated activation of cyclin-dependent kinases (Cdks) is generally believed to be the underlying mechanism since the function of p27 as an inhibitor of Cdks is firmly established. Here, we determined the effects of p27 inactivation on disease progression and Cdk activation in mouse liver tumorigenesis that originates from hepatocyte regenerative proliferation in response to chronic liver injury, an established etiology in most human liver cancer. Our results show that inactivation of p27 did not affect early-stage hepatocyte regenerative proliferation but promoted tumor cell proliferation and progression in the late stage of the disease. Interestingly, Cdc2 over-expression was observed in all and cyclin E1 was over-expressed in half of the late-stage tumors regardless of p27 status; and p27 inactivation led to significant activation of Cdk2 or Cdc2 only in half of the p27-deficient tumors. These results reveal a tumor suppressor role of p27 in chronic hepatocyte injury-induced liver tumorigenesis and, at the same time, the need to further study the mechanisms for tumor promotion by p27 inactivation.
Sun
Daqian
D
Department of Developmental and Molecular Biology, Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA..
Ren
Hao
H
Oertel
Michael
M
Sellers
Rani S
RS
Zhu
Liang
L
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics*; D018450:Disease Progression; D004789:Enzyme Activation; D017353:Gene Deletion; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000293:injuries / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic
C493961:Cdkn1b protein, mouse; D006514:Hepatitis B Surface Antigens; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2