The mechanism of malignant transformation of CADM1-positive lung adenocarcinoma

2016 Fiscal Year Annual Research Report

• Project/Area Number: 25460432
• Research Institution: Jichi Medical University
• Principal Investigator: 松原 大祐 自治医科大学, 医学部, 准教授 (80415554)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: CADM1 / RAPGEF2 / lung adenocarcinoma

Outline of Annual Research Achievements

Loss of the expression of a tumor suppressor cell adhesion molecule 1 (CADM1) is usually observed in invasive lung adenocarcinomas. However, some invasive high-grade adenocarcinomas overexpress CADM1. Here, we investigated the characteristics of CADM1-positive high-grade subtype. In this study, we found that lung adenocarcinoma cell lines expressing CADM1 frequently show low level expressions of bronchial epithelial markers, such as TTF-1 and CK7. Furthermore, these CADM1-positive cell lines co-express a RAP guanine exchange factor, RAPGEF2. Knockdown of RAPGEF2 reduced cell migration and RAP1 activity, which suggested that RAPGEF2 promoted cell migration through activation of RAP1. In addition, our knockdown experiments of RAPGEF2 indicate that RAPGEF2 reduces the tumor suppressor function of CADM1. Immunohistochemical analysis of lung adenocarcinoma cases (n=140) revealed that high level expression of RAPGEF2 correlated with high-grade subtype, low level expressions of bronchial epithelial markers, and worse prognosis especially in CADM1-positive lung adenocarcinomas. In conclusion, RAPGEF2 will get involved in the malignant phenotype of CADM1-positive high grade subtype.

Research Products

• [Journal Article] Identification of cell-type-specific mutations in nodal T-cell lymphomas. (2017)
  • Author(s): Nguyen TB, Sakata-Yanagimoto M, Asabe Y, Matsubara D, Kano J, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Izutsu K, Nakamura N, Takeuchi K, Miyoshi H, Ohshima K, Minowa T, Ogawa S, Noguchi M, Chiba S.
  • Journal Title: Blood Cancer Journal Volume: 7 Pages: －
  • DOI: 10.1038/bcj.2016.122
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pancreatic neuroendocrine tumor with metastasis to the spleen: a case report. (2017)
  • Author(s): Sakuma Y, Yasuda Y, Sata N, Hosoya Y, Shimizu A, Fujii H, Matsubara D, Fukushima N, Miki A, Maeno M, Lefor AK.
  • Journal Title: BMC Cancer Volume: 17 Pages: -
  • DOI: 10.1186/s12885-016-3020-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crohn's disease presenting as a ceco-urachal fistula. (2017)
  • Author(s): Tsukui H, Koinuma K, Morimoto M, Horie H, Lefor AK, Kagaya Y, Takahashi H, Yano T, Matsubara D, Yamamoto H, Sata N.
  • Journal Title: Clin J Gastroenterol Volume: 10 Pages: 32-36
  • DOI: 10.1007/s12328-016-0691-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 胸部の原発不明癌の鑑別 (2017)
  • Author(s): 松原 大祐
  • Journal Title: 病理と臨床 Volume: 35 Pages: 152-159
  • DOI: -
• [Journal Article] Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. (2016)
  • Author(s): Tominaga K, Shimamura T, Kimura N, Murayama T, Matsubara D, Kanauchi H, Niida A, Shimizu S, Nishioka K, Tsuji EI, Yano M, Sugano S, Shimono Y, Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa T, Tojo A, Miyano S, Gotoh N.
  • Journal Title: Oncogene Volume: 90 Pages: 6738-45
  • DOI: 10.1128/JVI.00846-16
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of YAP1 defines neuroendocrine differentiation of lung tumors. (2016)
  • Author(s): Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S, Isagawa T, Morikawa T, Shinozaki-Ushiku A, Goto Y, Nakano T, Tsuchiya T, Tsubochi H, Komura D, Aburatani H, Dobashi Y, Nakajima J, Endo S, Fukayama M, Sekido Y, Niki T, Murakami Y.
  • Journal Title: Cancer Science Volume: 107 Pages: 1527-1538
  • DOI: 10.1111/cas.13013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis. (2016)
  • Author(s): Maruzuru Y, Koyanagi N, Takemura N, Uematsu S, Matsubara D, Suzuki Y, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: Journal of Virology Volume: 90 Pages: 6738-45
  • DOI: 10.1128/JVI.00846-16
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. (2016)
  • Author(s): Ikenoue T, Terakado Y, Nakagawa H, Hikiba Y, Fujii T, Matsubara D, Noguchi R, Zhu C, Yamamoto K, Kudo Y, Asaoka Y, Yamaguchi K, Ijichi H, Tateishi K, Fukushima N, Maeda S, Koike K, Furukawa Y.
  • Journal Title: Scientific Reports Volume: 6:23899 Pages: －
  • DOI: 10.1038/srep23899
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 高悪性度神経内分泌腫瘍におけるYAP1 の欠失は，神経内分泌分化と薬剤感受性を決定づける (2016)
  • Author(s): 松原 大祐
  • Organizer: 第５７回 日本肺癌学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-12-19 – 2016-12-21
• [Presentation] 形態学的アプローチに基づくNon-TRU type 肺腺癌の解析：TFF-1 とTTF-1 の相互排他的な関係性について (2016)
  • Author(s): 松原 大祐
  • Organizer: 第５７回 日本肺癌学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-12-19 – 2016-12-21
• [Presentation] Inactivating mutations of the NKX2-1 gene in non-TRU-type lung cancer:identification through histology-driven approach (2016)
  • Author(s): 松原 大祐
  • Organizer: 第７５回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06 – 2016-10-08
• [Remarks] 自治医科大学統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/