title: Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas.
abstract: Emerging evidence confirms a central role of Akt in cancer. To evaluate the relative contribution of deregulated Akt and their clinicopathological significance in lung carcinomas, overexpression, activation of Akt and AKT gene increases were investigated. Immunohistochemical staining for 108 cases revealed overexpression of total Akt, Akt1, Akt2 and Akt3 in 61.1, 47.2, 40.7 and 23.1%, respectively, and phosphorylated Akt in 42.6% of cases. Expression of total Akt, Akt2 and Akt3 were frequently observed in small cell carcinoma, but phosphorylated Akt and Akt1 were more frequently observed in squamous cell carcinoma. FISH analysis to evaluate gene increases of AKT1-3 revealed amplification of AKT1 in 4.2% and AKT1 increase by polysomy of chromosome 14 in 27.3% of cases. For AKT2, amplification was observed in 3.2% and polysomy of chromosome 19 in 26.3% of cases. AKT3 increase was observed in 40.0% of cases only by polysomy of chromosome 1. Although "FISH-positive" AKT1 and AKT2 gene increases (amplification/high-level polysomy) were found exclusively in the cases overexpressing total Akt, Akt1 or Akt2, respectively, AKT3 increase was irrelevant of Akt3 expression. Statistically, expressions of Akt2, p-Akt and cytoplasmic-p-Akt were correlated with lymph node metastasis (P = 0.0479, P = 0.0371 and P = 0.0310, respectively). Although AKT1 and AKT2 gene increase showed positive correlation with, or trend towards a positive correlation with tumor size (P = 0.0430, P = 0.0590, respectively), AKT3 did not. In conclusion, Akt isoforms are differentially involved in the pathological phenotype of lung carcinoma in a diverse manner. Because abnormality of Akt1/AKT1 and Akt2/AKT2 correlated with clinicopathological profiles, Akt1/2-specific targeting may open a novel therapeutic window for the group showing Akt deregulation.
authors: Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors: Yoh
authors: Y
authors: Dobashi
authors: Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors: Hiroyoshi
authors: H
authors: Tsubochi
authors: Second Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Hirochika
authors: H
authors: Matsubara
authors: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Jun
authors: J
authors: Inoue
authors: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Johji
authors: J
authors: Inazawa
authors: Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors: Shunsuke
authors: S
authors: Endo
authors: Department of Molecular and Cellular Pathology, Kanazawa University School of Medicine, Ishikawa, Japan.
authors: Akishi
authors: A
authors: Ooi
mesh_terms: D002869:Chromosome Aberrations; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*
chemical_list: C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; gene amplification; isoforms; lung carcinoma; lymph node metastasis