Increased ectodomain shedding of lung-epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema

• Project/Area Number: 25860302
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Kinki University
• Principal Investigator: HAGIYAMA Mitsuru 近畿大学, 医学部, 助教 (60632718)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 細胞障害 / 接着分子 / プロテアーゼ / アポトーシス / 肺気腫 / 細胞外切断 / CADM1 / shedding

Outline of Final Research Achievements

Alveolar epithelial cell apoptosis and proteolysis play central roles in the pathogenesis of emphysema, but molecular mechanisms underlying these two events are not yet clearly understood. CADM1 is a lung-epithelial cell adhesion molecule and generates membrane-associated C-terminal fragments (CTFs) through protease-mediated ectodomain shedding. Western blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by TUNEL assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express αCTF by shedding inducers; phorbol ester and trypsin. Immunofluorescence and TUNEL assays revealed that CADM1-αCTF was localised to mitochondria and increased cell apoptosis. CADM1 shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing αCTF that accumulated in mitochondria.

Research Products

• [Journal Article] Increased ectodomain shedding of cell adhesion molecule 1 from pancreatic islets in type 2 diabetic pancreata: correlation with hemoglobin A1c levels. (2014)
  • Author(s): Inoue T, et al
  • Journal Title: Plos One Volume: 9 Issue: 6 Pages: 00-00
  • DOI: 10.1371/journal.pone.0100988
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased ectodomain shedding of lung-epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema. (2014)
  • Author(s): Mimae T, et al
  • Journal Title: Thorax Volume: 69 Issue: 3 Pages: 223-231
  • DOI: 10.1136/thoraxjnl-2013-203867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] α- Parvin, a pseudopodial constituent, promotes cell motility and is associated with lymph node metastasis of lobular breast carcinoma. (2014)
  • Author(s): Ito M, Hagiyama M, Mimae T, Inoue T, Kato T, Yoneshige A, Nakanishi J, Kondo T, Okada M, Ito A.
  • Journal Title: Breast Cancer Res Treat Volume: 144 Issue: 1 Pages: 59-69
  • DOI: 10.1007/s10549-014-2859-0
  • Peer Reviewed / Open Access
• [Journal Article] Increased expression of cell adhesion molecule 1 by mast cells as a cause of enhanced nerve-mast cell interaction in a hapten-induced mouse model of atopic dermatitis (2013)
  • Author(s): Man Hagiyama, Takao Inoue, Tadahide Furuno, Takanori Iino, Saori Itami, Mamoru Nakanishi, H. Asada, Yoichiroh Hosokawa and Akihiko Ito
  • Journal Title: Brit. J. Dermato Volume: (In press) Issue: 4 Pages: 771-778
  • DOI: 10.1111/bjd.12108
  • Peer Reviewed
• [Journal Article] Cell adhesion molecule 1 is a new osteoblastic cell adhesion molecule and a diagnostic marker for osteosarcoma. (2013)
  • Author(s): Inoue T, Hagiyama M, Enoki E, Sakurai MA, Tan A, Wakayama T, Iseki S, Murakami Y, Fukuda K, Hamanishi C, Ito A.
  • Journal Title: Life Sci Volume: 92 Issue: 1 Pages: 91-99
  • DOI: 10.1016/j.lfs.2012.10.021
  • Peer Reviewed
• [Journal Article] Estimating cell adhesion strength. (2013)
  • Author(s): Hosokawa Y, Iino T, Hagiyama M, Ito A.
  • Journal Title: SPIE Newsroom Volume: -
  • DOI: 10.1117/2.1201302.004619
• [Presentation] アクチン結合性アダプター蛋白α-parvinは偽足突起構成要素であり、小葉乳癌のリンパ節転移に関与する (2014)
  • Author(s): 萩山満、伊藤彰彦
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] マスト細胞における接着分子CADM1の発現上昇：アトピー性皮膚炎のストレス感受性への関与 (2014)
  • Author(s): 萩山満、井上敬夫、米重あづさ、伊藤彰彦
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島（広島国際会議場、ANAクラウンプラザホテル広島）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] エキシマレーザーを用いた癌細胞偽足突起のプロテオミクス (2013)
  • Author(s): 萩山満、伊藤彰彦
  • Organizer: 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] エキシマレーザーによる癌細胞偽足突起の選択的採取とプロテオミクス (2013)
  • Author(s): 萩山満、伊藤彰彦
  • Organizer: 日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Femtosecond laser-assisted estimation of time evolution of cell-cell adhesion force between neurite and mast cell. (2013)
  • Author(s): Iino T, Hagiyama M, Furuno T, Ito A, Hosokawa Y.
  • Organizer: Lasers and Electro-Optics Pacific Rim
  • Place of Presentation: Kyoto
• [Book] 細胞の接着・遊走を司る偽足突起の単離とプロテオミクス 先端レーザー微細加工技術の応用 (2013)
  • Author(s): 伊藤彰彦, 萩山満, 細川陽一郎
  • Total Pages: 5
  • Publisher: 医学書院
• [Book] Mast cells (Version 3.0) (2013)
  • Author(s): Oboki K, Hagiyama M, Inoue T, Ito A.
  • Publisher: eLS