Regulation of gene expression of BRAK, a human tumor progression suppressing chemokine

• Project/Area Number: 19592162
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Kanagawa Dental College
• Principal Investigator: HATA Ryuuichirou Kanagawa Dental College, 歯学部, 教授 (10014276)
• Co-Investigator(Kenkyū-buntansha): OZAWA Shigeyuki 神奈川歯科大学, 歯学部, 特別研究員 (40434394) ; MAEHATA Yojiro 神奈川歯科大学, 歯学部, 助教 (80410009) ; TAKAGAKI Yuko 神奈川歯科大学, 歯学部, 准教授 (60050689) ; バワール ウジャール 神奈川歯科大学, 歯学部, 特別研究員 (50433339) ; 加藤 靖正 神奈川歯科大学, 歯学部, 講師 (50214408) ; 倉田 俊一 神奈川歯科大学, 歯学部, 客員教授 (60140901)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 口腔癌 / 腫瘍抑制因子 / BRAK / CXCL14 / 転写制御 / ゲフィチニブ / 頭頚部癌 / 上皮増殖因子阻害剤 / 腫瘍抑制遺伝子 / CXCL14遺伝子 / AP-1結合配列 / 頭頸部癌 / ケモカイン / MAPキナーゼ / 上皮増殖因子

Research Abstract

口腔癌の進展を抑制する因子としてケモカインBRAK/CXCL14を見いだした。腫瘍組織ではBRAK/CXCL14の発現量が低下しているが、腫瘍細胞にBRAK/CXCL14を強制的に発現させると、腫瘍形成能が低下した。また、T細胞を欠損したヌードマウスに腫瘍を移植後、上皮増殖因子受容体の阻害剤であるゲフィチニブ(イレッサ)を飲ませると腫瘍内のBRAK/CXCL14の発現が上昇し、かつ腫瘍が小さくなった。BRAK/CXCL14の発現が腫瘍抑制に重要であると考えられるのでその遺伝子の発現制御機構を明らかにした。

Research Products

• [Journal Article] Roles of Collagen Molecules in Growth and Differentiation of Human Osteoblasts (2009)
  • Author(s): Maehata Y, Lee MC, Hata I
  • Journal Title: J Oral Bioscience 51(2) Pages: 72-80
  • NAID: 10027104531
  • Peer Reviewed
• [Journal Article] Heparin promotes the growth of human embryonic stem cells in a defined serum-free medium (2008)
  • Author(s): Furue MK, Na J, Jackson JP, Okamoto T, Jones M, Baker D, Hata. Moore HD, Sato JD, Andrews PW
  • Journal Title: Proc Natl Acad Sci USA 105(36) Pages: 13409-14
  • Peer Reviewed
• [Journal Article] p63(TP63)elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and DeltaN isoforms (2008)
  • Author(s): Okuyama T, Kurata S, Tomimori Y, Fukunishi N, Sato S, Osada M, Tsukinoki K, Jin HF, Yamashita A, Ito M, Kobayashi S, Hata R.I, Ikawa Y, Katoh I.
  • Journal Title: Oncogene 27 Pages: 308-317
  • Peer Reviewed
• [Journal Article] Heparin promotes the growth of human embryonic stem cells in adefined serum-free medium. (2008)
  • Author(s): Furue MK., et al.
  • Journal Title: Proc Natl Acad Sci USA. 105 Pages: 13409-13414
  • Peer Reviewed
• [Journal Article] Chemokine BRAK Stimulates Apoptosis of Oral Squamous Cell Carcinoma Caused by Gefitinib. (2008)
  • Author(s): Ito S., et al.
  • Journal Title: Bull. Kanagawa Dent. Col. 36 Pages: 87-89
  • Peer Reviewed
• [Journal Article] Determination of Transcriptional Start Site and Promoter Sequence of BRAK/CXCL14 Gene. (2008)
  • Author(s): Komori R., et al.
  • Journal Title: Bull. Kanagawa Dent. Col. 36 Pages: 90-92
  • Peer Reviewed
• [Journal Article] p63(TP63)elicits strong trans-activation of the MFG-E8/lactadherin/BA46 genethrough interactions between the TA and DeltaN isoforms. (2008)
  • Author(s): Okuyama T., et. al.
  • Journal Title: Oncogene 27(3) Pages: 308-317
  • Peer Reviewed
• [Journal Article] Integrins regulate mouse embryonic stem cell self-renewal (2007)
  • Author(s): Hayashi Y, Furue MK, Okamoto T, Ohnuma K, Myoishi Y, Fukuhara Y, Abe T, Sato JD, Hata, Asashima M
  • Journal Title: Stem Cells 25(12) Pages: 3005-15
  • Peer Reviewed
• [Journal Article] Acidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanoma (2007)
  • Author(s): Kato Y, Ozawa S, Tsukuda M, Kubota E, Miyazaki K, St-Pierre Y, Hata
  • Journal Title: FEBS J 274(12) Pages: 3171-83
  • Peer Reviewed
• [Journal Article] Type III collagen is essential for growth acceleration of human osteoblastic cells by ascorbic acid 2-phosphate (2007)
  • Author(s): Maehata Y, Takamizawa S, Ozawa S, Izukuri K, Kato Y, Sato S, Lee MC, Kimura A, Hata
  • Journal Title: long-acting vitamin C derivative. Matrix Biol 26(5) Pages: 371-81
  • Peer Reviewed
• [Journal Article] Integrins regulate mouse embryonic stem cell self-renewal. (2007)
  • Author(s): Hayashi Y., et. al.
  • Journal Title: Stem Cells 12 Pages: 3005-3015
  • Peer Reviewed
• [Journal Article] Acidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanoma. (2007)
  • Author(s): Kato Y., et. al.
  • Journal Title: FEBS Journal 274(12) Pages: 3171-3183
  • Peer Reviewed
• [Journal Article] Type III collagen is essential for growth acceleration of human osteoblastic cells by ascorbic acid 2-phosphate, a long-acting vitamin C derivative. (2007)
  • Author(s): Maehata Y., et. al.
  • Journal Title: Matrix Biology 26 Pages: 371-378
  • Peer Reviewed
• [Presentation] Functional Analysis of Promoter of Human BRAK/CXCL14, A Tumor Suppressor. (2009)
  • Author(s): Komori R., et al.
  • Organizer: 87^<th>IADR/Unilever Hatton Awards Competition Senior. (Basic. Science)
  • Place of Presentation: Miami, Florida, USA.
  • Year and Date: 2009-03-31
• [Presentation] The BRAK box is opening (2009)
  • Author(s): Hata. R
  • Organizer: Yokosuka Science Festa 2009
  • Place of Presentation: Shonan Village Center
• [Presentation] Production of BRAK knockout mice (2009)
  • Author(s): Nobuyuki Yajima, Ryu-Ichiro Hata
  • Organizer: Yokosuka Science Festa 2009
  • Place of Presentation: Shonan Village Center
• [Presentation] Suppression of growth of Lewis lung carcinoma cell xenografts in BRAK transgenic mouse : Production of cancer resistant mouse (2009)
  • Author(s): Kazuhito Izukuri, Kenji Suzuki, Shigeyuki Ozawa, Eiro Kubota, Ryu-Ichiro Hata
  • Organizer: Yokosuka Science Festa 2009
  • Place of Presentation: Shonan Village Center
• [Presentation] Chemokine BRAK stimulates apoptosis elicited by gefitinib in oral squamous cell carcinoma (2009)
  • Author(s): Shin Ito, Shigeyuki Ozawa, Naoto Shiiki, Keiichi Tsukinoki, Eiro Kubota, Yasumasa Kato, Takahide Taguchi, Yukari Imagawa-Ishiguro, Mamoru Tsukuda, and Ryu-Ichiro Hata
  • Organizer: Yokosuka Science Festa 2009
  • Place of Presentation: Shonan Village Center
• [Presentation] Expression of BRAK/CXCL14 is associated with antitumor efficacy of gefitinib in head and neck squamous cell carcinoma (2009)
  • Author(s): Shigeyuki Ozawa, Yasumasa Kato, Shin Ito, Reika Komori, Kenji Suzuki, Keiichi Tsukinoki, Yojiro Maehata, Takahide Taguchi, Yukari Imagawa-Ishiguro, Mamoru Tsukuda, Eiro Kubota, and Ryu-Ichiro Hata
  • Organizer: Yokosuka Science Festa 2009
  • Place of Presentation: Shonan Village Center
• [Presentation] Functional analysis of promoter region of human BRAK/CXCL14, a tumor progression suppressor (2009)
  • Author(s): Reika Komori, Shigeyuki Ozawa, Yasumasa Kato, Hisaaki Shinji, Shigenari Kimoto, and Ryu-Ichiro Hata
  • Organizer: Yokosuka Science Festa 2009
  • Place of Presentation: Shonan Village Center
• [Presentation] Functional Analysis of Promoter of Human BRAK/CXCL14, A Tumor Suppressor (2009)
  • Author(s): Reika Komori Shigeyuki Ozawa, Yasumasa Kato, Hisaaki Shinji, Shigenari Kimoto, and Ryu-Ichiro Hata
  • Organizer: 87^<th> General Session & Exhibition of the IADR
  • Place of Presentation: Miami, Florida
• [Presentation] A new mechanism of tumor suppression by gefitinib in HNSCC (2009)
  • Author(s): Shigeyuki Ozawa, Yasumasa Kato, Shin Ito, Reika Komori, Naoto Shiiki, Keiichi Tukinoki, Satoru Ozono, Yojiro Maehata, Takahide Taguchi, Yukari Imagawa-Ishiguro, Mamoru Tsukuda, Eiro Kubota, and Ryu-Ichiro Hata
  • Organizer: 87^<th> General Session & Exhibition of the IADR
  • Place of Presentation: Miami, Florida
• [Presentation] Regulation of BRAK/CXCL14 gene expression by MAP kinase signaling (2008)
  • Author(s): Ryu-Ichiro Hata, Shigeyuki Ozawa, Yasumasa Kato, Shin Ito, Reika Komori, Yojiro Maehata, Eiro Kubota
  • Organizer: AACR Special Conference : Chemical and Biological Aspects of Inflammation and Cancer
  • Place of Presentation: Oahu, Hawaii
• [Presentation] Expression of BRAK/CXCL14 is a marker for gefitinib responsiveness of human head and neck squamous cell carcinoma (2008)
  • Author(s): Ryu-Ichiro Hata, Shigeyuki Ozawa, Yasumasa Kato, Shin Ito, Reika Komori, Naoto Shiiki, Keiichi Tsukinoki, Satoru Ozono, Yojiro Maehata, Takahide Taguchi, Yukari Imagawa-Ishiguro, Mamoru Tsukuda, Eiro Kubota
  • Organizer: American Association for Cancer Research Annual Meeting 2008
  • Place of Presentation: San Diego, CA
• [Presentation] Determination of transcription start-site of CXCL14/BRAK in squamous cell carcinoma (2008)
  • Author(s): Reika Komori Shigeyuki Ozawa, Yasumasa Kato, Hisaaki Shinji, Shigenari Kimoto, and Ryu-Ichiro Hata
  • Organizer: 86^<th> International Association of Dental Research
  • Place of Presentation: Toronto, Canada
• [Presentation] p38 signaling up-regulates BRAK expression in squamous cell carcinoma (2008)
  • Author(s): Shigeyuki Ozawa, Yasumasa Kato, Shin Ito, Reika Komori, Yojiro Maehata, Eiro Kubota, and Ryu-Ichiro Hata.
  • Organizer: 86^<th> International Association of Dental Research
  • Place of Presentation: Toronto, Canada
• [Presentation] Gefitinib (ZD1839, Iressa) reduced tumor volume through BRAK/CXCL14 expression in head and neck squamous cell carcinoma (2008)
  • Author(s): Shigeyuki Ozawa Yasumasa Kato, Shin Ito, Reika Komori, Naoto Shiiki, Keiichi Tukinoki, Satoru Ozono, Yojiro Maehata, Takahide Taguchi, Yukari Imagawa-Ishiguro, Mamoru Tsukuda, Eiro Kubota, and Ryu-Ichiro Hata
  • Organizer: KEYSTONE SYMPOSIUM on chemokine and chemokine receptors
  • Place of Presentation: Keystone, Colorado
• [Presentation] Expression of BRAK/CXCL14 is a marker for gefitinib responsiveness ofhuman head and neck squamous cell carcinoma. (2008)
  • Author(s): Hata R., et al.
  • Organizer: AACR Annual Meeting.
  • Place of Presentation: San Diego, CA. USA.
• [Presentation] TypeIII collagen regulates growth of human osteoblastic cells. (2008)
  • Author(s): Maehata Y., et al.
  • Organizer: 86^<th> IADR.
  • Place of Presentation: Toronto, Canada.
• [Presentation] p38 signaling up-regulates BRAK expression in squamous cell carcinoma. (2008)
  • Author(s): Ozawa S., et al.
  • Organizer: 86^<th> IADR.
  • Place of Presentation: Toronto, Canada.
• [Presentation] Determination of transcription start-site of CXCL14/BRAK in squamouscell carcinoma. (2008)
  • Author(s): Komori R., et al.
  • Organizer: 86^<th> IADR.
  • Place of Presentation: Toronto, Canada.
• [Presentation] Distinct roles of NF-κB Subunits in Matrix Metalloproteinase-9 Expression Induced by Acidic Extracellular pH. (2008)
  • Author(s): Kato Y., et al.
  • Organizer: MRS AACR.
  • Place of Presentation: Vancouver, Canada.
• [Presentation] Regulation of BRAK/CXCL14 gene expression by MAP kinase signaling. (2008)
  • Author(s): Hata R., et al.
  • Organizer: AACR Special Conference : Chemical and Biological Aspects of Inflammation and Cancer.
  • Place of Presentation: Ko Olina Oahu, Hawaii, USA.
• [Presentation] Reciprocal Effects of Oxidative Stress on the Gene Expression of Il-8/CXCL8 and BRAK/CXCL14 in Human Head and Neck Squamous Cell Carcinoma (2007)
  • Author(s): Maehata Y, Takamizawa S, Ozawa S, Kato Y, Yoshino F, Kobayashi K, Takahashi S, Todoki K, Hata, Lee M-C.
  • Organizer: The 4th Joint Meeting of the Society For Free Radical Research Australia and Japan
  • Place of Presentation: Kyoto, Japan
• [Presentation] Gefitinib (ZD1839, Iressa) Reduces Tumor Volume Through BRAK/CXCL14 Expression (2007)
  • Author(s): Hata R, Ozawa S, Kato Y, Ito S, Komori R, Shiiki N, Tsukinoki K, Ozono S, Maehata Y, Taguchi T, Imagawa-Ishiguro Y, Tsukuda M, Kubota E
  • Organizer: ASCB
  • Place of Presentation: Washington DC, USA
• [Presentation] Gefitinib stimulates expression of BRAK, a tumor suppressing chemokine and suppresses growth of tumor xenograft (2007)
  • Author(s): Hata R, Ozawa S, Kato Y, Komori R, Maehata Y, Kubota E, Tsukuda M
  • Organizer: GRC on Cancer Genetics & Epigenetics IL CIOCCO
  • Place of Presentation: Italy
• [Presentation] Gefitinib stimulates expression of BRAK, a tumor suppressing chemokine and suppresses growth of tumor xenograft. (2007)
  • Author(s): Hata R., et. al.
  • Organizer: GRC on Cancer Genetics & Epigenetics
  • Place of Presentation: Italy
• [Presentation] Reconsideration of collagen function in human osteoblasts. (2007)
  • Author(s): Hata R., et. al.
  • Organizer: Gordon Research Conference on Collagen
  • Place of Presentation: USA
• [Presentation] Type III collagen is essential for growth acceleration of human osteoblastic cells. (2007)
  • Author(s): Maehata Y., et. al.
  • Organizer: 7th PPCTSS.
  • Place of Presentation: Australia
• [Presentation] Gefitinib(ZD1839, Iressa)Reduces Tumor Volume Through BRAK/CXCL14E xpression. (2007)
  • Author(s): Hata R., et. al.
  • Organizer: ASCB
  • Place of Presentation: USA
• [Presentation] Development of Defined Medium for Human ES Cell Culture. (2007)
  • Author(s): Furue M K., et. al.
  • Organizer: 5th Annual Meeting of International Society for Stem Cell Research
  • Place of Presentation: Australia
• [Remarks] 畑隆一郎、小澤重幸、加藤靖正、小森令賀、前畑洋次郎、久保田英朗 : 新しい発想による内在性癌進展抑制遺伝子の探索と発見~ケモカインBRAK/CXCL14はin vivoにおいて腫瘍抑制作用を示す~バイオアカデミックフォーラム、2007年6月20日~22日、東京ビッグサイト、東京テレビ
• [Remarks] 小森令賀がIADR Hatton Awardで2008年度Travel Awardを受賞した。また、YokosukaScience Festa 2009でYoung Investigator Awardを受賞した、前畑洋次郎が2008年度歯科基礎医学会賞を受賞した。また、2009年度結合組織学会大高賞を受賞した。畑隆一郎が2009年度に本結合組織学会学術賞を受賞した。