Novel cancer therapeutic target, epithelial membrane protein 1 (EMP1), investigation of the molecular mechanism inducing invasion and metastasis

• Project/Area Number: 17K08657
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Akio Shimizu 滋賀医科大学, 医学部, 助教 (30769279)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: がん / 浸潤 / 転移 / EMP1 / がん転移 / Copine-III / Rac1 / 細胞運動 / 浸潤・転移 / 細胞間相互作用

Outline of Final Research Achievements

Metastatic cancer is frequently led to fatality. Thus, understanding of the underlying mechanism is important to reduce it. The expression of epithelial membrane protein 1 (EMP1) was upregulated in prostate cancer cells by contacting with surrounding stroma cells. EMP1 has four transmembrane domains. Overexpression of EMP1 in prostate cancer, LNCaP cells (EMP1-LNCaP cells) enhanced invasiveness, which was also observed in other types of cancer cells. In in vivo analysis, EMP1-LNCaP cells implanted in the prostate metastasized to lymph nodes and the lung but the parental LNCaP did not. Next, copine-III was identified by usage of tandem mass spectrometry as a novel molecule binding to the intracellular region of EMP1. The EMP1-copine-III complex induced the signal via Src, Vav2, and Rac1, leading to the enhanced cancer cell migration and invasion. As clinical implications, increased EMP1 expression was observed in the samples from prostate cancer patients with higher Gleason scores.

Academic Significance and Societal Importance of the Research Achievements

本研究は、がん細胞と正常細胞の相互作用によってEMP1の発現が上昇することを明らかにし、浸潤・転移への寄与を明らかにした点に新規の学術的意義がある。EMP1は悪性度の高いがん患者検体においてその発現が上昇していたことを明らかにしたが、EMP1は細胞膜タンパク質であり、外部から抗体や薬剤などでその作用を阻害しやすいことは臨床応用へ進む上で大きな利点である。本研究の成果から、がんの治療標的あるいは分子マーカーとしてEMP1 は有用である可能性が示された。

Research Products

• [Journal Article] Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis (2020)
  • Author(s): Matsushima Shoko、Shimizu Akio、Kondo Manami、Asano Hirotsugu、Ueno Nobuhiro、Nakayama Hironao、Sato Naoko、Komeno Masahiro、Ogita Hisakazu、Kurokawa-Seo Misuzu
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 188-188
  • DOI: 10.1038/s41598-019-57040-3
  • Peer Reviewed / Open Access
• [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (2020)
  • Author(s): Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 5 Pages: 6399-6417
  • DOI: 10.1096/fj.201902991r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Pivotal Roles of the Epithelial Membrane Protein Family in Cancer Invasiveness and Metastasis (2019)
  • Author(s): Ahmat Amin MKB, Shimizu A, Ogita H.
  • Journal Title: Cancers Volume: 11 Issue: 11 Pages: 1620-1620
  • DOI: 10.3390/cancers11111620
  • NAID: 120006766857
  • Peer Reviewed / Open Access
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap (2018)
  • Author(s): Shimizu A, Zankov DP, Kurokawa-Seo M, Ogita H.
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 4 Pages: 1203-1203
  • DOI: 10.3390/ijms19041203
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1 (2018)
  • Author(s): Ahmat Amin MKB, Shimizu A, Zankov DP, Sato A, Kurita S, Ito M, Maeda T, Yoshida T, Sakaue T, Higashiyama S, Kawauchi A, Ogita H.
  • Journal Title: Oncogene Volume: 37 Issue: 40 Pages: 5416-5434
  • DOI: 10.1038/s41388-018-0286-0
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of dipeptidyl peptidase III in cleavage of angiotensin II and its clinical implication (2017)
  • Author(s): 清水昭男、扇田久和
  • Journal Title: 生化学 Volume: 89 Issue: 3 Pages: 449-452
  • DOI: 10.14952/SEIKAGAKU.2017.890449
  • ISSN: 0037-1017
  • Year and Date: 2017-06-25
  • Peer Reviewed / Open Access
• [Journal Article] Differential Effects of Myocardial Afadin on Pressure Overload-Induced Compensated Cardiac Hypertrophy (2017)
  • Author(s): Zankov, D.P., Sato, A., Shimizu, A., and Ogita, H.
  • Journal Title: Circulation Journal Volume: 81 Issue: 12 Pages: 1862-1870
  • DOI: 10.1253/circj.CJ-17-0394
  • NAID: 130006219260
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] ジペプチジルペプチダーゼ-3が糖尿病での腎機能悪化を抑制 (2019)
  • Author(s): 大東親生、清水昭男、Xiaoling Pang、扇田久和
  • Organizer: 第65回 日本生化学会 近畿支部例会
• [Presentation] Epithelial membrane protein 1はRac1を活性化してがん細胞の遊走を促進させがんの浸潤・転移を促進する (2019)
  • Author(s): 清水昭男、Mohammad Khusni Bin Ahmat Amin、佐藤朗、扇田久和
  • Organizer: 第92回 日本生化学会
• [Presentation] ジペプチジルペプチダーゼ-3が 糖尿病での心腎機能悪化を抑制 (2019)
  • Author(s): 清水昭男、扇田久和
  • Organizer: CVMW2019 心血管代謝週間
• [Presentation] 糖尿病性腎症に対するジぺプチジルペプチターゼIIIの保護作用 (2018)
  • Author(s): 山口有汰、清水昭男、Xiaoling Pang、Dimitar P. Zankov、石田哲生、扇田久和
  • Organizer: 第65回日本生化学会近畿支部例会（兵庫医科大学）
• [Presentation] Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Diabetic Nephropathy (2018)
  • Author(s): Xiaoling Pang、Akio Shimizu、Dimitar P. Zankov、Akira Sato、Tetsuo Ishida、Hisakazu Ogita
  • Organizer: 第91回日本生化学会大会（京都国際会議場）
• [Presentation] Deciphering Signaling Pathway of a Novel Cancer Pro-invasive and -metastatic Molecule, Epithelial Membrane Protein 1 (2017)
  • Author(s): Mohammad Khusni Ahamad bin amin、Akio Shimizu、Dimitar P. Zankov、Akira Sato、 Hisakazu Ogita
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] VEGF-A/Neuropilin-1シグナルを阻害する膜透過性ペプチドは、腫瘍の成長と転移を抑制する (2017)
  • Author(s): 吉田 亜佑美、清水昭男、門之園哲哉、近藤科江、瀬尾美鈴
  • Organizer: 第21回 日本がん分子標的治療学会学術集会
• [Presentation] Critical Role of Myocardial Afadin in Cardiac Protection during Chronic Mechanical Overload (2017)
  • Author(s): Dimitar P. Zankov、Akio Shimizu、Akira Sato、Hisakazu Ogita
  • Organizer: 第64回 日本生化学会 近畿支部例会
• [Remarks] 滋賀医科大学 分子病態生化学部門 ホームページ
  • URL: http://www.shiga-med.ac.jp/~hqbioch2/