The role of HB-EGF in cancer cell proliferation and malignancy

• Project/Area Number: 23240126
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka University
• Principal Investigator: MEKADA Eisuke 大阪大学, 微生物病研究所, 教授 (20135742)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥49,140,000 (Direct Cost: ¥37,800,000、Indirect Cost: ¥11,340,000); Fiscal Year 2013: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2012: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2011: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
• Keywords: EGFファミリー / 増殖因子 / 増殖抑制 / EGF受容体 / 心臓弁 / EGFリセプター / ＨＢ-ＥＧＦ / ＥＧＦ受容体

Outline of Final Research Achievements

We have studied on the role of HB-EGF in cancer cell proliferation and malignancy. In 2011, we have studied the role of HB-EGF expressing at tumor stroma in uterine cervical cancer. We have shown that HB-EGF expressed in stroma and PDGF expressed in cancer cells contribute to the reciprocal interaction of cancer cells with cancer-associated fibroblasts and promote cancer cell proliferation in a paracrine manner, providing an insight for the novel combinatorial therapy. In 2012-2013, we have studied on the molecular mechanism of HB-EGF-inducing growth inhibition. In cardiac valve, HB-EGF inhibits the proliferation of mesenchymal cells. The study indicated that HB-EGF is expressed in cardiac epithelial cells and secreted toward the mesenchymal cells in developing heart valve tissue, where HB-EGF inhibits mesenchymal cell proliferation. P38 MAPK and JNK are involved in this process. Further study may provide a new paradigm for cancer therapy.

Research Products

• [Journal Article] Co-occurrence of tetraspanin and ROS generators: Conservation in protein cross-linking and other developmental processes. (2013)
  • Author(s): Moribe H, Mekada E.
  • Journal Title: Worm Volume: 2 Issue: 2 Pages: 23415-23416
  • DOI: 10.4161/worm.23415
  • Peer Reviewed / Open Access
• [Journal Article] Metastasis Suppressor Tetraspanin CD82/KAI1 Regulates Ubiquitylation of Epidermal Growth Factor Receptor. (2013)
  • Author(s): Odintsova E, van Niel G, Conjeaud H, Raposo G, Iwamoto R, Mekada E, Berditchevski F.
  • Journal Title: J Biol Chem. Volume: 288 Issue: 36 Pages: 26323-26334
  • DOI: 10.1074/jbc.m112.439380
  • Peer Reviewed / Open Access
• [Journal Article] Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. (2013)
  • Author(s): Takemura T, Yoshida Y, Kiso S, Kizu T, Furuta K, Ezaki H, Hamano M, Egawa M, Chatani N, Kamada Y, Imai Y, Higashiyama S, Iwamoto R, Mekada E, Takehara T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 437 Issue: 2 Pages: 185-191
  • DOI: 10.1016/j.bbrc.2013.05.097
  • Peer Reviewed
• [Journal Article] Development of anti-HB-EGF immunoliposomes for the treatment of breast cancer. (2012)
  • Author(s): K. Nishikawa, T. Asai, H. Shigematsu, K. Shimizu, H. Kato, Y. Asano, S. Takashima, E. Mekada, N. Oku, T. Minamino
  • Journal Title: J. Control. Release Volume: 160 Issue: 2 Pages: 274-280
  • DOI: 10.1016/j.jconrel.2011.10.010
  • Peer Reviewed
• [Journal Article] MIG-13 controls anteroposterior cell migration by interacting with UNC-71/ADM-1 and SRC-1 in Caenorhabditis elegans (2012)
  • Author(s): Masuda H, Nakamura, Takata N, Itoh B, Hirose T, Moribe H, Mekada E, Okada M
  • Journal Title: FEBS Lett 2012 Volume: 586(6) Issue: 6 Pages: 740-6
  • DOI: 10.1016/j.febslet.2012.01.031
  • Peer Reviewed
• [Journal Article] Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice. (2012)
  • Author(s): Takemura, T., YoshidaY., Kiso, S., Saji, Y., Ezaki, H., Hamano, M., Kizu, T., Egawa, M., Chatani, N., Furuta, K., Kamada, Y., Iwamoto, R., Mekada, E., Higashiyama, S., Hayashi, N. and Takehara, T.
  • Journal Title: Hepatol Res Volume: 43 Issue: 4 Pages: 384-393
  • DOI: 10.1111/j.1872-034x.2012.01074.x
  • NAID: 10031194550
  • Peer Reviewed
• [Journal Article] Tetraspanin is required for generation of reactive oxygen species by the dual oxidase system in Caenorhabditis elegans. (2012)
  • Author(s): Moribe, H., Konakawa, R., Yoneda, T., Koga, D., Ushiki, T., Nakamura K. and Mekada, E.
  • Journal Title: PLoS Genet. Volume: 8 Issue: 9 Pages: e1002957-e1002957
  • DOI: 10.1371/journal.pgen.1002957
  • Peer Reviewed
• [Journal Article] Soluble heparin-binding EGF-like growth factor (HB-EGF) detected by newly developed immuno-PCR method is a clear-cut serological biomarker for ovarian cancer. (2012)
  • Author(s): Kasai N, Kobayashi K, Shioya S, Yoshikawa Y, Yotsumoto F, Miyamoto S, Mekada E, Enokizono J.
  • Journal Title: Am J Transl Res. Volume: 4 Pages: 415-421
  • Peer Reviewed
• [Journal Article] A novel anti-human HB-EGF monoclonal antibody with multiple anti-tumor mechanisms against ovarian cancer cells. (2011)
  • Author(s): Miyamoto, S.
  • Journal Title: Clinical Cancer Res. Volume: 17 Pages: 6733-6741
  • Peer Reviewed
• [Journal Article] HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers. (2011)
  • Author(s): Murata, T.
  • Journal Title: Cancer Res. Volume: 71 Pages: 6633-6664
  • Peer Reviewed
• [Journal Article] Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells. (2011)
  • Author(s): Koshikawa N.
  • Journal Title: Cancer Sci. Volume: 102 Pages: 111-116
  • Peer Reviewed
• [Presentation] 子宮頚癌ではHB-EGFとPDGFを介して癌細胞と癌関連線維芽細胞が相互作用し、癌細胞の増殖を促進する (2011)
  • Author(s): 村田卓也
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] The role of tetraspanins in the dual oxidase system of C.elegans and humans. (2011)
  • Author(s): Eisuke Mekada
  • Organizer: FASEB Summer Research Conferences Membrane Organization by Molecular Scaffolds.
  • Place of Presentation: Saxtons River, Vermont (U.S.A.)
  • Invited
• [Presentation] FAKのFERMﾄﾞﾒｲﾝのﾘﾝ酸化によるHB-EGF依存的細胞増殖制御 (2011)
  • Author(s): 水島寛人
  • Organizer: 第63回日本細胞生物学会大会
  • Place of Presentation: 札幌
• [Presentation] HB-EGF細胞質内ﾌﾗｸﾞﾒﾝﾄは破骨細胞の分化を負に制御する (2011)
  • Author(s): 中村尚志
  • Organizer: 第63回日本細胞生物学会大会
  • Place of Presentation: 札幌
• [Presentation] ﾃﾄﾗｽﾊﾟﾆﾝによる活性酸素産生の制御 (2011)
  • Author(s): 森部弘樹
  • Organizer: 第63回日本細胞生物学会大会
  • Place of Presentation: 札幌
• [Presentation] Clinical development of the diphtheria toxin mutant CRM197 for cancer therapy. (2011)
  • Author(s): Eisuke Mekada
  • Organizer: ETOX15 European Workshop on Bacterial Protein Toxins.
  • Place of Presentation: Oslo (Norway)
  • Invited
• [Remarks] 大阪大学 微生物病研究所 細胞機能分野 目加田研究室
  • URL: http://cell-biology.biken.osaka-u.ac.jp/MekadaLabHP/Home.html