The mechanism of malignant transformation of CADM1-positive lung adenocarcinoma

• Project/Area Number: 25460432
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Jichi Medical University (2015-2016); The University of Tokyo (2013-2014)
• Principal Investigator: Matsubara Daisuke 自治医科大学, 医学部, 准教授 (80415554)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: CADM1 / RAPGEF2 / RAP1 / non-TRU type / lung adenocarcinoma / RAPGE2 / EMT / 肺腺癌 / PRMT5

Outline of Final Research Achievements

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. Furthermore, these CADM1-positive cell lines co-express 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 Issue: 1 Pages: e516-e516
  • DOI: 10.1038/bcj.2016.122
  • Peer Reviewed / Open Access / 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 Issue: 1 Pages: 37-37
  • 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 Issue: 1 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
• [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: J Virol. Volume: 90(15) Issue: 15 Pages: 6738-6745
  • DOI: 10.1128/jvi.00846-16
  • Peer Reviewed / Open Access / 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 Issue: 10 Pages: 1527-1538
  • DOI: 10.1111/cas.13013
  • Peer Reviewed / Open Access / 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: Sci Rep Volume: 印刷中 Issue: 1 Pages: 23899-23899
  • DOI: 10.1038/srep23899
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent loss of the expression of multiple subunits of the SWI/SNF complex in large cell carcinoma and pleomorphic carcinoma of the lung. (2015)
  • Author(s): Yoshimoto T, Matsubara D, Nakano T, Tamura T, Endo S, Sugiyama Y, Niki T.
  • Journal Title: Pathology international Volume: 35 Issue: 11 Pages: 595-602
  • DOI: 10.1111/pin.12350
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma (2015)
  • Author(s): Shin Saito, Kazue Morishima, Takashi Ui, Hiroko Hoshino, Daisuke Matsubara, Shumpei Ishikawa, Hiroyuki Aburatani, Masashi Fukayama, Yoshinori Hosoya, Naohiro Sato, Alan K Lefor, Yoshikazu Yasuda and Toshiro Niki
  • Journal Title: BMC cancer Volume: 15 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s12885-015-1065-8
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical analysis of the expression of E-cadherin and ZEB1 in non-small cell lung cancer. (2014)
  • Author(s): Matsubara D, Kishaba Y, Yoshimoto T, Sakuma Y, Sakatani T, Tamura T, Endo S, Sugiyama Y, Murakami Y, Niki T
  • Journal Title: Pathology International Volume: 64 Issue: 11 Pages: 560-568
  • DOI: 10.1111/pin.12214
  • Peer Reviewed / Open Access
• [Journal Article] Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. (2014)
  • Author(s): Ibrahim R, Matsubara D, Osman W, Morikawa T, Goto A, Morita S, Ishikawa S, Aburatani H, Takai D, Nakajima J, Fukayama M, Niki T, Murakami Y
  • Journal Title: Hum Pathol. Volume: 45 Issue: 7 Pages: 1397-405
  • DOI: 10.1016/j.humpath.2014.02.013
  • Peer Reviewed / Open Access
• [Journal Article] Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma. (2014)
  • Author(s): Saito S, Morishima K, Ui T, Matsubara D, Tamura T, Oguni S, Hosoya Y, Sata N, Lefor AT, Yasuda Y, Niki T.
  • Journal Title: Oncology Reports Volume: 32 Issue: 1 Pages: 348-354
  • DOI: 10.3892/or.2014.3216
  • Peer Reviewed / Open Access
• [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
• [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
• [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
• [Presentation] The role of RAPGEF2 in CADM1-positive high-grade lung adenocarcinoma. (2015)
  • Author(s): Shu-Jen Shiu, Daisuke Matsubara, Teppei Morikawa, KJun Nakajima, Masashi Fukayama, Toshiro Niki, Yoshinori Murakami
  • Organizer: 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya Congress Center (Nagoya)
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] Loss of YAP1 defines neuroendocrine differentiation of lung tumor. (2015)
  • Author(s): Matsubara D, Ito T, Tanaka I, Makiya K, Kumagai Y, Sue J, Shumpei I, Isagawa T, Morikawa T, Ushiku A, Goto Y, Nakano T, Tsuchiya T, Aburatani H, Dobashi Y, Nakajima J, Endo S, Fukayama M, Sekido Y, Niki T, and Murakami Y
  • Organizer: 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya Congress Center (Nagoya)
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] Expression pattern of YAP1 in primary lung adenocarcinomas; correlation with pathologic features and prognosis. (2014)
  • Author(s): 2.Daisuke Matsubara, Takeshi Ito, Ichidai Tanaka, Teppei Morikawa, Jun Nakajima, Masashi Fukayama, Toshiro Niki, Yoshitaka Sekido, Yoshinori Murakami.
  • Organizer: 73th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition (2014)
  • Author(s): Matsubara D, Ibrahim RA, Osman W, Morikawa T, Morita S, Ishikawa S, Aburatani H, Fukayama M, Niki T, Murakami Y
  • Organizer: AACR
  • Place of Presentation: サンディエゴ、アメリカ
• [Presentation] 1.Expression of PRMT5 in lung adenocarcinoma: correlation with pathologic features and prognosis (2013)
  • Author(s): Ibrahim RA, Matsubara D, Osman W, Morikawa T, Morita S, Ishikawa S, Aburatani H, Fukayama M, Niki T, Murakami Y
  • Organizer: 72th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
• [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/
• [Remarks] 自治医大統合病理ホームページ
  • URL: http://www.jichi.ac.jp/pathol/
• [Remarks] 自治医科大学病理学講座統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/
• [Remarks] 最近の学会発表
  • URL: http://www.jichi.ac.jp/pathol/index.php?%E6%9C%80%E8%BF%91%E3%81%AE%E5%AD%A6%E4%BC%9A%E7%99%BA%E8%A1%A8
• [Remarks] 最近の発表論文
  • URL: http://www.jichi.ac.jp/pathol/index.php?%E6%9C%80%E8%BF%91%E3%81%AE%E7%99%BA%E8%A1%A8%E8%AB%96%E6%96%87