Analysis of membrane form of EGF family growth factors in the skin carcinogenesis using tissue-specific transgenic mice

• Project/Area Number: 21591434
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Ehime University
• Principal Investigator: SHIRAKATA Yuji 愛媛大学, 医学部附属病院, 准教授 (50226320)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 遺伝子改変 / マウス / HB-EGF / EGFR / carcinogenesis / テトラサイクリン / トランス活性化 / shedding阻害

Research Abstract

In order to clarify the role of HB-EGF in skin carcinogenesis, I produced the keratinocyte-specific HB-EGF deficient mouse and the keratinocyte-specific tetracycline-inducible HB-EGF transgenic mouse, and then chemical and ultraviolet induced carcinogenesis studies were performed. Papilloma and squamous carcinoma were detected at an early stage in HB-EGF transgenic mice compared to control. Conversely, there was little tumor generating in HB-EGF deficient mice. Taking together, overexpression of HB-EGF in vivo plays important roles in the pathogenesis of skin tumor formation.

Research Products

• [Journal Article] Targeted overexpression of Angptl6/angiopoietin-related growth factor in the skin promotes angiogenesis and lymphatic vessel enlargement in response to ultraviolet B (2012)
  • Author(s): Okazaki H, Hirakawa S, Shudou M, Nakaoka Y, Shirakata Y, Miyata K, Oike Y, Hashimoto K, Sayama K.
  • Journal Title: J Dermatol. J Dermatol Volume: 39(4) Pages: 366-74
  • NAID: 10031184909
  • Peer Reviewed
• [Journal Article] Epidermogenesis in a skin wound deep through the basement membrane contributes to scar formation (2012)
  • Author(s): Yang L, Hashimoto K, Shirakata Y.
  • Journal Title: J Dermatol Sci Volume: 65 Pages: 224-226
  • Peer Reviewed
• [Journal Article] IFN-αEnhances IL-22 Receptor Expression in Keratinocytes : A Possible Role in the Development of Psoriasis (2012)
  • Author(s): Tohyama M, Yang L, Hanakawa Y, Dai X, Shirakata Y, Sayama K.
  • Journal Title: J Invest Dermatol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin (2012)
  • Author(s): Nakayama H, Fukuda S, Inoue H, Nishida-Fukuda H, Shirakata Y, Hashimoto K, Higashiyama S.
  • Journal Title: Mol Biol Cell Volume: (in press)
  • Peer Reviewed
• [Journal Article] Targeted overexpression of Angpt16/angiopoietin-related growth factor in the skin promotes angiogenesis and lymphatic vessel enlargement in response to ultraviolet B (2012)
  • Author(s): Okazaki H, et al
  • Journal Title: J Dermatol Volume: 39 Issue: 4 Pages: 366-74
  • DOI: 10.1111/j.1346-8138.2011.01396.x
  • Peer Reviewed
• [Journal Article] Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents (2012)
  • Author(s): Yang L, et al
  • Journal Title: J Dermatol Sci Volume: 65 Issue: 1 Pages: 50-7
  • DOI: 10.1016/j.jdermsci.2011.10.008
  • Peer Reviewed
• [Journal Article] IFN-α Enhances IL-22 Receptor Expression in Keratinocytes : A Possible Role in the Development of Psoriasis (2012)
  • Author(s): Tohyama M, et al
  • Journal Title: J Invest Dermatol Volume: (印刷中) Issue: 7 Pages: 1933-1935
  • DOI: 10.1038/jid.2011.468
  • Peer Reviewed
• [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin (2012)
  • Author(s): Nakayama H, et al
  • Journal Title: Mol Biol Cell Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Nuclear translocation of phosphorylated STAT3 regulates VEGF-A-induced lymphatic endothelial cell migration and tube formation (2011)
  • Author(s): Okazaki H, Tokumaru S, Hanakawa Y, Shiraishi K, Shirakata Y, Dai X, Yang L, Tohyama M, Hashimoto K, Sayama K.
  • Journal Title: Biochem Biophys Res Commun Volume: 412(3) Pages: 441-5
  • Peer Reviewed
• [Journal Article] Nuclear translocation of phosphorylated STAT3 regulates VEGF-A-induced lymphatic endothelial cell migration and tube formation (2011)
  • Author(s): Okazaki H, et al
  • Journal Title: Biochem Biophys Res Commun Volume: 412 Issue: 3 Pages: 441-5
  • DOI: 10.1016/j.bbrc.2011.07.111
  • Peer Reviewed
• [Journal Article] Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents (2010)
  • Author(s): Yang L, Hashimoto K, Tohyama M, Okazaki H, Dai X, Hanakawa Y, Sayama K, Shirakata Y.
  • Journal Title: J Dermatol Sci Volume: 65 Pages: 50-7
  • Peer Reviewed
• [Journal Article] Auto-and cross-induction by betacellulin in epidermal keratinocytes (2010)
  • Author(s): Shirakata Y, Tokumaru S, Sayama K, Hashimoto K.
  • Journal Title: J Dermatol Sci Volume: 58(2) Pages: 162-4
  • NAID: 10027400978
  • Peer Reviewed
• [Journal Article] Regulation of epidermal keratinocytes by growth factors (2010)
  • Author(s): Shirakata Y.
  • Journal Title: J Dermatol Sci Volume: 59(2) Pages: 73-80
  • NAID: 10027401602
  • Peer Reviewed
• [Journal Article] Inflammatory mediator TAK1 regulates hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice (2010)
  • Author(s): Sayama K, Kajiya K, Sugawara K, Sato S, Hirakawa S, Shirakata Y, Hanakawa Y, Dai X, Ishimatsu-Tsuji Y, Metzger D, Chambon P, Akira S, Paus R, Kishimoto J, Hashimoto K.
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] E2 Polyubiquitin-conjugating enzyme Ubc13 in keratinocytes is essential for epidermal integrity (2010)
  • Author(s): Sayama K, Yamamoto M, Shirakata Y, Hanakawa Y, Hirakawa S, Dai X, Tohyama M, Tokumaru S, Shin MS, Sakurai H, Akira S, Hashimoto K.
  • Journal Title: J Biol Chem Volume: 285 Pages: 30042-9
  • Peer Reviewed
• [Journal Article] PPARγmediates innate immunity by regulating the 1α, 25-dihydroxyvitamin D3 induced hBD-3 and cathelicidin in human keratinocytes (2010)
  • Author(s): Dai X, Sayama K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yang L, Hirakawa S, Hashimoto K.
  • Journal Title: J Dermatol Sci Volume: 60(3) Pages: 179-86
  • Peer Reviewed
• [Journal Article] Auto- and cross-induction by betacellulin in epidermal keratinocytes. (2010)
  • Author(s): Shirakata Y, Tokumaru S, Sayama K, Hashimoto K
  • Journal Title: Journal of Dermatological Science Volume: 58 Pages: 162-164
  • NAID: 10027400978
  • Peer Reviewed
• [Journal Article] Inflammatory mediator TAK1 regulates hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice. (2010)
  • Author(s): Sayama K, Kajiya K, Sugawara K, Sato S, Hirakawa S, Shirakata Y, Hanakawa Y, Dai X, Ishimatsu-Tsuji Y, Metzger D, Chambon P, Akira S, Paus R, Kishimoto J, Hashimoto K
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] E2 Polyubiquitin-conjugating enzyme Ubc13 in keratinocytes is essential for epidermal integrity. (2010)
  • Author(s): Sayama K, Yamamoto M, Shirakata Y, Hanakawa Y, Hirakawa S, Dai X, Tohyama M, Tokumaru S, Shin MS, Sakurai H, Akira S, Hashimoto K
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 30042-30049
  • Peer Reviewed
• [Journal Article] PPARγ mediates innate immunity by regulating the 1α,25-dihydroxyvitamin D3 induced hBD-3 and cathelicidin in human keratinocytes. (2010)
  • Author(s): Dai X, Sayama K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yang L, Hirakawa S, Hashimoto K
  • Journal Title: Journal of Dermatological Science Volume: 60 Pages: 179-186
  • NAID: 10027841095
  • Peer Reviewed
• [Journal Article] Regulation of epidermal keratinocytes by growth factors. (2010)
  • Author(s): Shirakata Y
  • Journal Title: Journal of Dermatological Science Volume: 59 Pages: 73-80
  • NAID: 10027401602
  • Peer Reviewed
• [Journal Article] Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications (2009)
  • Author(s): Sotozono C, Ueta M, Koizumi N, Inatomi T, Shirakata Y, Ikezawa Z, Hashimoto K, Kinoshita S.
  • Journal Title: Ophthalmology Volume: 116 Pages: 685-90
  • Peer Reviewed
• [Journal Article] The influence of hepatic damage on serum soluble Fas ligand levels of patients with drug rashes (2009)
  • Author(s): Tohyama M, Shirakata Y, Sayama K, Hashimoto K.
  • Journal Title: J Allergy Clin Immunol Volume: 123 Pages: 971-2
  • Peer Reviewed
• [Journal Article] Alteration of TLR3 pathways by glucocorticoids may be responsible for immunosusceptibility of human corneal epithelial cells to viral infections (2009)
  • Author(s): Hara Y, Shiraishi A, Kobayashi T, Kadota Y, Shirakata Y, Hashimoto K, Ohashi Y.
  • Journal Title: Mol Vis Volume: 15 Pages: 937-48
  • Peer Reviewed
• [Journal Article] IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression (2009)
  • Author(s): Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, Tokumaru S, Okazaki H, Sayama K, Hashimoto K.
  • Journal Title: Eur J Immunol Volume: 39 Pages: 2279-88
  • Peer Reviewed
• [Journal Article] Living Skin Equivalents Constructed Using Human Amnions as a Matrix (2009)
  • Author(s): Yang L, Shirakata Y, Tokumaru S, Xiuju D, Tohyama M, Hanakawa Y, Hirakawa S, Sayama K, Hashimoto K.
  • Journal Title: J Dermatol Sci Volume: 56 Pages: 188-95
  • NAID: 10027398843
  • Peer Reviewed
• [Journal Article] Nodal Lymphangiogenesis and Metastasis : Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease (2009)
  • Author(s): Hirakawa S, Detmar M, Kerjaschki D, Nagamatsu S, Matsuo K, Tanemura A, Kamata N, Higashikawa K, Okazaki H, Kameda K, Nishida-Fukuda H, Mori H, Hanakawa Y, Sayama K, Shirakata Y, Tohyama M, Tokumaru S, Katayama I, Hashimoto K.
  • Journal Title: Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease Volume: 175 Pages: 2235-48
  • Peer Reviewed
• [Journal Article] Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications (2009)
  • Author(s): Sotozono C, Ueta M, Koizumi N, Inatomi T, Shirakata Y, Ikezawa Z, Hashimoto K, Kinoshita S.
  • Journal Title: Ophthalmology 116 Pages: 685-90
  • Peer Reviewed
• [Journal Article] The influence of hepatic damage on serum soluble Fas ligand levels of patients with drug rashes (2009)
  • Author(s): Tohyama M, Shirakata Y, Sayama K, Hashimoto K
  • Journal Title: J Allergy Clin Immunol 123 Pages: 971-2
  • Peer Reviewed
• [Journal Article] Alteration of TLR3 pathways by glucocorticoids may be responsible for immunosusceptibility of human corneal epithelial cells to viral infections (2009)
  • Author(s): Hara Y, Shiraishi A, Kobayashi T, Kadota Y, Shirakata Y, Hashimoto K, Ohashi Y
  • Journal Title: Mol Vis 15 Pages: 937-48
  • Peer Reviewed
• [Journal Article] IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytesvia increased IL-22 receptor expression (2009)
  • Author(s): Tohyama M, Hanakawa Y, Shinakata Y, Dai X, Yang L, Hirakawa S, Tokumaru S, Okazaki H, Sayama K, Hashimoto K
  • Journal Title: Eur J Immunol 39 Pages: 2279-88
  • Peer Reviewed
• [Journal Article] Living Skin Equivalents Constructed Using Human Amnions as a Matrix (2009)
  • Author(s): Yang L, Shirakata Y, Tokumaru S, Xiuju D, Tohyama M, Hanakawu Y, Hirakawa S, Sayama K, Hashimoto K
  • Journal Title: J Dermatol Sci 56 Pages: 188-95
  • NAID: 10027398843
  • Peer Reviewed
• [Journal Article] Nodal Lymphangiogenesis and Metastasis : Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease (2009)
  • Author(s): Hirakawa S, Shirakata Y, 他
  • Journal Title: Am J Pathol 175 Pages: 2235-48
  • Peer Reviewed
• [Presentation] Deletion of SOCS3 in the epidermis causes impaired skin wound healing in vivo (2010)
  • Author(s): Shirakata Y, Yang L, Tsuda T, Tohyama M, Miyawaki S, Kameda K, Sayama K, Yoshimura A, Hashimoto K
  • Organizer: The 40^h Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Successful treatment of severe pemphigus vulgaris with high-dose intravenous immunoglobulin (2010)
  • Author(s): Shirakata Y, Ishikawa M, Murakami S, Hashimoto K
  • Organizer: 9^<th> Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: Weimar, Germany
• [Presentation] Deletion of SOCS3 in the epidermis causes impaired skin wound healing in vivo. (2010)
  • Author(s): Shirakata Y, Yang L, Tsuda T, Tohyama M, Miyawaki S, Kameda K, Sayama K, Yoshimura A, Hashimoto K
  • Organizer: The 40^h Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Successful treatment of severe pemphigus vulgaris with high-dose intravenous immunoglobulin. (2010)
  • Author(s): Shirakata Y, Ishikawa M, Murakami S, Hashimoto K
  • Organizer: 9^<th> Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: Weimar, Germany
• [Presentation] Simple method of constructing living skin equivalent using human amnion as dermal matrix (2009)
  • Author(s): Shirakata Y, Yang L, Sayama K, and Hashimoto K
  • Organizer: The 39^<th> Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Budapest, Hungary
• [Presentation] Development of a new skin equivalent using de-epithelialized amnion membrane (2009)
  • Author(s): Shirakata Y and Hashimoto K
  • Organizer: The 4^<th> Joint Meeting of Japanese Dermatological Association and Australasian College of Dermatologists
  • Place of Presentation: Sapporo, Japan
• [Presentation] Inflammatory mediator TAK1 regulates hair follicle cycling (2009)
  • Author(s): Sayama K, Shirakata Y, Ishimatsu-Tsuji Y, Kajiya K, Hirakawa S, Sugawara K, Chambon P, Akira S, Paus R, Kishimoto J, and Hashimoto K
  • Organizer: The 69^<th> Annual Meeting of Society for Investigative Dermatology
  • Place of Presentation: Montreal, Canada
• [Presentation] Simple method of constructing living skin equivalent using human amnionas dermal matrix (2009)
  • Author(s): Shirakata Y, Yang L, Sayama K, Hashimoto K
  • Organizer: The 39^<th> Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Budapest, Hungary
• [Presentation] Development of a new skin equivalent using de-epithelialized amnion membrane (2009)
  • Author(s): Shirakata Y, Hashimoto K
  • Organizer: The 4^<th> Joint Meeting of Japanese Dermatological Association and Australasian College of Dermatolog
  • Place of Presentation: Sapporo