title: The difference in Ezrin-pAkt signaling axis between lepidic and papillary predominant invasive adenocarcinomas of the lung.
abstract: OBJECTIVE
  Histologic classification of invasive lung adenocarcinomas by predominant subtype has prognostic value. Papillary predominant adenocarcinoma (PPA) reportedly shows poorer prognosis than lepidic predominant adenocarcinoma (LPA); however, biological differences between PPA and LPA are unclear. The purpose of this study was to clarify biological differences between PPA and LPA.
  
  
  METHODS
  Clinicopathological characteristics of invasive 62 PPAs and 117 LPAs smaller than 30 mm were investigated. Furthermore, we compared immunochemical staining scores of 9 molecular markers (E-cadherin, S100A4, fibronectin, integrinβ1, ezrin, GLUT1, ALDH1, SOX2 and Nanog) between PPA and LPA. We performed Western blot analysis using ezrin shRNA-knockdown lung adenocarcinoma cell lines to examine whether molecules that are highly expressed in PPA, such as ezrin, affect pAkt. Finally, we performed immunochemical staining to compare pAkt expression level in PPA and LPA.
  
  
  RESULTS
  Lymphovascular and pleural invasion and lymph node metastasis were significantly more often detected in PPA than in LPA (lymphatic permeation: 31 vs 3 %, vascular invasion: 35 vs 3 %, pleural invasion: 29 vs 5 %, lymph node metastasis: 18 vs 1 %; all P < 0.01). Immunohistochemical (IHC) study revealed that expression score of ezrin was significantly higher in PPA than in LPA (38.3 vs 15.0; P < 0.01). The level of pAkt decreased in shEzrin-induced PC-9 and A549 cancer cells. Moreover, the IHC staining score of pAkt was significantly higher in PPA than in LPA (13.3 vs 0.0; P < 0.01).
  
  
  CONCLUSIONS
  Our results show that the activation of the ezrin-pAkt signaling axis is associated with the more aggressive clinicopathological features of PPA compared with LPA.
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Department of General Thoracic Surgery, Juntendo University School of Medicine, 3-1-3, Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hata
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yoshida
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Hibiki
authors.initials: H
authors.lastname: Udagawa
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Keiju
authors.initials: K
authors.lastname: Aokage
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Department of General Thoracic Surgery, Juntendo University School of Medicine, 3-1-3, Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. gishii@east.ncc.go.jp.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099149:Ezrin
keywords: Ezrin; Lepidic predominant adenocarcinoma; Lung adenocarcinoma; Papillary predominant adenocarcinoma; Predominant subtype; pAkt