title: Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms.
abstract: Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2(-/-) mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1(-/-) nor Akt2(-/-) mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2(-/-) mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC.
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Wan-Ni
authors.initials: WN
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Xiao-Ding
authors.initials: XD
authors.lastname: Peng
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Jeon
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Department of Pathology, College of Medicine, Cancer Center, University of Illinois Hospital and Health Science Chicago, Chicago, IL 60612, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Guzman
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA; Research & Development Section, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. Electronic address: nhay@uic.edu.
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
mesh_terms: D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006130:Growth Disorders / Q000235:genetics; D006505:Hepatitis / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000097:blood; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020033:Protein Isoforms / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D015850:Interleukin-6; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C577686:interleukin-6, mouse; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt