消化器がん個性診断法の開発

• 研究課題/領域番号: 17015042
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 慶應義塾大学
• 研究代表者: 坂元 亨宇 慶應義塾大学, 医学部, 教授 (40221270)
• 研究期間 (年度): 2005 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 66,700千円 (直接経費: 66,700千円); 2009年度: 13,300千円 (直接経費: 13,300千円); 2008年度: 13,400千円 (直接経費: 13,400千円); 2007年度: 13,400千円 (直接経費: 13,400千円); 2006年度: 13,400千円 (直接経費: 13,400千円); 2005年度: 13,200千円 (直接経費: 13,200千円)
• キーワード: 多段階発がん / 早期肝細胞がん / 浸潤性膵管がん / 神経浸潤 / 移植モデル / 遺伝子発現プロファイル / プロテオーム / 浸潤 / synuclein-Y / Schwann細胞 / 予後因子 / 悪性度 / CD74

研究概要

Cyclase-associated protein (CAP) 2が、肝細胞がんの多段階発がん過程の早期がんの段階から悪性化に伴って発現亢進することを見出した。同ホモログCAP1が膵がんで高率に過剰発現していること、細胞運動・浸潤に関わり予後不良因子となることを示した。免疫不全マウスにてヒト膵がん神経浸潤モデルを作成し、高神経浸潤群と低浸潤群間の遺伝子発現プロファイルを比較し、CD74が神経浸潤に関与することを初めて示した。プロテオーム解析ならびに機能解析から、Synuclein-γが膵がん神経浸潤ならびに転移に関与すること、独立した予後不良因子であることを見出した。

研究成果

• [雑誌論文] Bmi-1 gene is upregulated in early-stage hepatocellular carcinoma and correlates with ATP-binding cassette transporter B1 (ABCB1) expression. (2010)
  • 著者名/発表者名: Effendi K, Mori T, Komuta M, Masugi Y, Du W, Sakamoto M
  • 雑誌名: Cancer Sci (in press)
  • 査読あり
• [雑誌論文] Endothelin-2 is upregulated in basal cell carcinoma under control of Hedgehog signaling pathway. (2010)
  • 著者名/発表者名: Tanese K, Fukuma M, Ishiko A, Sakamoto M
  • 雑誌名: Biochem Biophys Res Commun 391 ページ: 486-491
  • 査読あり
• [雑誌論文] Bmi-1 gene is upregulated in early-stage hepatocellular carcinoma and correlates with ATP-binding cassette transporter B1 (ABCB1) expression. (2010)
  • 著者名/発表者名: Effendi K, Mori T, Komuta M, Masugi Y, Du W, Sakamoto M.
  • 雑誌名: Cancer Sci (in press)
  • 査読あり
• [雑誌論文] Endothelin-2 is upregulated in basal cell carcinoma under control of Hedgehog signaling pathway. (2010)
  • 著者名/発表者名: Tanese K, Fukuma M, Ishiko A, Sakamoto M.
  • 雑誌名: Biochem Biophys Res Commun. 391 ページ: 486-491
  • 査読あり
• [雑誌論文] Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility. (2009)
  • 著者名/発表者名: Yamazaki K, Takamura M, Masugi Y, Mori T, Du W, Hibi T, Hiraoka N, Ohta T, Ohki M, Hirohashi S, Sakamoto M
  • 雑誌名: Lab Invest 89(4) ページ: 425-432
  • 査読あり
• [雑誌論文] Construction of human monoclonal single-chain Fv antibodies against small-cell lung cancer by phage display libraries derived from cell-immunized SCID mice engrafted with human peripheral blood lymphocytes. (2009)
  • 著者名/発表者名: Douguchi J, Hashiguchi A, Sakamoto M
  • 雑誌名: Proteomics Clin Appl 3 ページ: 1265-1272
  • 査読あり
• [雑誌論文] Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer. (2009)
  • 著者名/発表者名: Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tanabe M, Aiura K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y, Sakamoto M
  • 雑誌名: Clin Cancer Res 15(8) ページ: 2864-2871
  • 査読あり
• [雑誌論文] Early HCC : diagnosis and molecular markers. (2009)
  • 著者名/発表者名: Sakamoto M.
  • 雑誌名: J Gastroenterol. 44Suppl19 ページ: 108-111
  • NAID: 10024364289
  • 査読あり
• [雑誌論文] Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility. (2009)
  • 著者名/発表者名: Yamazaki K, Takamura M, Masugi Y, Mori T, Du W, Hibi T, Hiraoka N, Ohta T, Ohki M, Hirohashi S, Sakamoto M.
  • 雑誌名: Lab Invest. 89(4) ページ: 425-432
  • 査読あり
• [雑誌論文] Pathologic diagnosis of early hepatocellular carcinoma : a report of the international consensus group for hepatocellular neoplasia. (2009)
  • 著者名/発表者名: International Consensus Group for Hepatocellular Neoplasia.
  • 雑誌名: Hepatology. 49(2) ページ: 658-664
  • 査読あり
• [雑誌論文] Intraductal carcinoma component as a favorable prognostic factor in biliary tract carcinoma. (2009)
  • 著者名/発表者名: Ojima H, Kanai Y, Iwasaki M, Hiraoka N, Shimada K, Sano T, Sakamoto Y, Esaki M, Kosuge T, Sakamoto M, Hirohashi S.
  • 雑誌名: Cancer Sci. 100(1) ページ: 62-70
  • NAID: 10025141316
  • 査読あり
• [雑誌論文] Construction of human monoclonal single-chain Fvantibodies against small-cell lung cancer by phagedisplay libraries derived from cell-immunized SCID mice engrafted with human peripheral blood lymphocytes. (2009)
  • 著者名/発表者名: Douguchi J, Hashiguchi A, Sakamoto M.
  • 雑誌名: Proteomics Clin Appl 3 ページ: 1265-1272
  • 査読あり
• [雑誌論文] Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer. (2009)
  • 著者名/発表者名: Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tanabe M, Aiura K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y, Sakamoto M.
  • 雑誌名: Clin Cancer Res 15(8) ページ: 2864-2871
  • 査読あり
• [雑誌論文] Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility (2009)
  • 著者名/発表者名: Yamazaki K, Takamura M, Masugi Y, Mori T, Du W, Hibi T, Hiraoka N, Ohta T, Ohki M, Hirohashi S, Sakamoto M
  • 雑誌名: Lab Invest (in press)
  • 査読あり
• [雑誌論文] Synuclein-y is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer (2009)
  • 著者名/発表者名: Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tanabe M, Aiura K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y. Sakamoto M
  • 雑誌名: Clin Cancer Res (in press)
  • 査読あり
• [雑誌論文] G-Protein-Coupled Receptor GPR49 is Up-regulated in Basal Cell Caricinoma and Promotes Cell Proliferation and Tumor Formation. (2008)
  • 著者名/発表者名: Tanese K, Fukuma M, Yamada T, Mori T, Yoshikawa T, Watanabe W, Ishiko A, Amagai M, Nihsikawa T, Sakamoto M
  • 雑誌名: Am J Pathol 173 ページ: 835-843
  • 査読あり
• [雑誌論文] Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma. (2008)
  • 著者名/発表者名: Kamiya K, Hayashi Y, Douguchi J, Hashiguchi A, Yamada T, Izumi Y, Watanabe M, Kawamura M, Horinouchi H, Shimada N, Kobayashi K, Sakamoto M
  • 雑誌名: Mod Pathol 21 ページ: 992-1001
  • 査読あり
• [雑誌論文] Expression Profile of Early Lung Adenocarcinoma: Identification of MRP3 as a Molecular Marker for Early Progression. (2008)
  • 著者名/発表者名: Hanada S, Maeshima A, Matsuno Y, Ohta T, Ohki M, Yoshida T, Hayashi Y, Yoshizawa Y, Hirohashi S, Sakamoto M
  • 雑誌名: J Pathol 216 ページ: 75-82
  • 査読あり
• [雑誌論文] Establishment of an ovarian metastasis model and possible involvement of E-cadherin down-regulation in the metastasis. (2008)
  • 著者名/発表者名: Kuwabara Y, Yamada T, Yamazaki K, Du W, Banno K, Aoki D, Sakamoto M
  • 雑誌名: Cancer Sci 99 ページ: 1933-1939
  • NAID: 10024011784
  • 査読あり
• [雑誌論文] G-Protein-Coupled Receptor GPR49 is Up-regulated inBasal Cell Caricinoma and Promotes Cell Proliferation and Tumor Formation (2008)
  • 著者名/発表者名: Tanese K, Fukuma M, Yamada T, Mori T, Yoshikawa T, Watanabe W, Ishiko A, Amagai M, Nihsikawa T, Sakamoto M
  • 雑誌名: Am J Pathol 173 ページ: 835-843
  • 査読あり
• [雑誌論文] Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma (2008)
  • 著者名/発表者名: Kamiya K, Hayashi Y, Douguchi J, Hashiguchi A, Yamada T, Izumi Y, Watanabe M, Kawamura M, Horinouchi H, Shimada N, Kobayashi K, Sakamoto M
  • 雑誌名: Mod Pathol 21 ページ: 992-1001
  • 査読あり
• [雑誌論文] Expression Profile of Early Lung Adenocarcinoma : Identification of MRP3 as a Molecular Marker for Early Progression (2008)
  • 著者名/発表者名: Hanada S, Maeshima A, Matsuno Y, Ohta T, Ohki M, Yoshida T, Hayashi Y, Yoshizawa Y, Hirohashi S, Sakarnnin M
  • 雑誌名: J Pathol 216 ページ: 75-82
  • 査読あり
• [雑誌論文] Establishment of an ovarian metastasis model and possible involvement of E-cadherin down-regulation in the metastasis (2008)
  • 著者名/発表者名: Kuwabara Y, Yamada T, Yamazaki K, Du W, Banno K, Aoki D, Sakamoto M
  • 雑誌名: Cancer Sci 99 ページ: 1933-1939
  • NAID: 10024011784
  • 査読あり
• [雑誌論文] Reconstitution of Schwannian Stroma in Neuroblastomas Using Human Bone Marrow Stromal Cells (2008)
  • 著者名/発表者名: Du W, Hozumi N, Sakamoto M, Hata J, Yamada T
  • 雑誌名: AmJ Pathol 173 ページ: 1153-1164
  • 査読あり
• [雑誌論文] Specific Expression of Hepatocyte Nuclear Factor-1βin the Ovarian Clear Cell Adenocarcinoma and its Application to Cytological Diagnosis. (2007)
  • 著者名/発表者名: Higashiguchi A, Yamada T, Susumu N, Mori T, Suzuki A, Aoki D, Sakamoto M
  • 雑誌名: Cancer Sci 98 ページ: 387-391
  • 査読あり
• [雑誌論文] Gene therapy of liver timors with human liver-specific nanoparticles. (2007)
  • 著者名/発表者名: Iwasaki Y, Ueda M, Yamada T, Kondo A, Seno M, Tanizawa K, Kuroda S, Sakamoto M. Kitaiima M
  • 雑誌名: Cancer Gene Therapy 14 ページ: 74-81
  • 査読あり
• [雑誌論文] Specific Expression of Hepatocyte Nuclear Factor。1Bin theOvarian Clear Cell Adenocarcinoma and its Application to Cytological Diagnosis. (2007)
  • 著者名/発表者名: Higashiguchi A, Yamada T, Susumu N, Mori T, SuzukiA, Aoki D, Sakamoto M
  • 雑誌名: Cancer Sci 98 ページ: 387-391
  • 査読あり
• [雑誌論文] Genome-wide array-based comparative genomic hybridizationanalysis of pancreatic adenocarcinoma: Identification of genti indicators that predict patient outcome. (2007)
  • 著者名/発表者名: Loukopoulos P, Shibata T, Katoh H, Kokubu A, Saka moto M, Yamazaki K, Kosuge T, Kanai Y, Hosoda F, Imoto I, Ohki M, Inazawa J, Hirohashi S
  • 雑誌名: Cancer Sci 98 ページ: 392-400
  • 査読あり
• [雑誌論文] Efficient immortalization of primary human cells by p16INK4a-specific short hairpin RNA or Bmi-1, combined with introduction of hTERT. (2007)
  • 著者名/発表者名: Haga K, Ohno S, Yugawa T, Narisawa-Saito M, FujitaM, Sakamoto M, GallowayDA, Kiyono T
  • 雑誌名: Cancer Sci 98 ページ: 147-154
  • 査読あり
• [雑誌論文] Establishment of a novel childhood acute myeloid leukemia cell line, KOPM-88, containing partial tandem duplication of theMLL gene and an in vivo model for childhood acute myeloid leukemia using NOD/SCID mice. (2007)
  • 著者名/発表者名: Hayashi M, Kondoh K, Nakata Y; Kinoshita A, ]Mori T, Takahashi T, Sakamoto M, Yamada T:
  • 雑誌名: Br J Haematol 137 ページ: 221-232
  • 査読あり
• [雑誌論文] Gene therapy of liver timors with human liver-specific nanoparticles (2007)
  • 著者名/発表者名: Iwasaki Y, Ueda M, Yamada T, Kondo A, Seno M, Tanizawa K, Kuroda S, Sakamoto M, Kitajima M
  • 雑誌名: Cancer Gene Therapy 14 ページ: 74-81
• [雑誌論文] Efficient immortalization of primary human cells by p16INK4a-specific short hairpin RNA or Bmi-1, combined with introduction of hTERT (2007)
  • 著者名/発表者名: Haga K, Ohno S, Yugawa T, Narisawa-Saito M, Fujita M, Sakamoto M, Galloway DA, Kiyono T
  • 雑誌名: Cancer Sci 98 ページ: 147-154
• [雑誌論文] Specific Expression of Hepatocyte Nuclear Factor-1 β in the Ovarian Clear Cell Adenocarcinoma and its Application to Cytological Diagnosis (2007)
  • 著者名/発表者名: Higashiguchi A, Yamada T, Susumu N, Mori T, Suzuki A, Aoki D, Sakamoto M
  • 雑誌名: Cancer Sci 98 ページ: 387-391
  • NAID: 10019481758
• [雑誌論文] Establishment of Perineural Invasion Models and Analysis of Gene Expression Revealed an Invariant Chain (CD74) as a Possible Molecule involved in Perineural Invasion in Pancreatic Cancer. (2006)
  • 著者名/発表者名: Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimazu M, Hirohashi S, Nimura Y, Sakamoto M
  • 雑誌名: Clin Cancer Res 12(8) ページ: 2419-2426
  • 査読あり
• [雑誌論文] Overexpression of cyclase-associated protein 2 in multistage hepatocarcinogenesis. (2006)
  • 著者名/発表者名: Shibata R, Mori T, Du W, Chuma M, Gotoh M, Shimazu M, Ueda M, Hirohashi S, Sakamoto M
  • 雑誌名: Clin Cancer Res 12(18) ページ: 5363-5368
  • 査読あり
• [雑誌論文] Establishment of Perineural Invasion Models and Analysis of Gene Expression Revealed an Invariant Chain (CD74) as a Possible Molecule involved in Perineural Invasion in Pancreatic Cancer (2006)
  • 著者名/発表者名: Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimazu M, Hirohashi S, Nimura Y, Sakamoto M
  • 雑誌名: Clin Cancer Res 12(8) ページ: 2419-2426
• [雑誌論文] CT Evalution of the Progression of Hypoattenuating Nodular Lesions in Virus-Related Chronic liver Disease (2006)
  • 著者名/発表者名: Takaysu K, Muramatsu Y, Mizuguchi Y, Okusaka T, Shimada K, Tkayama T, Sakamoto M
  • 雑誌名: AJR 187 ページ: 454-463
• [雑誌論文] Overexpression of cyclase-associated protein 2 in multistage hepatocarcinogenesis (2006)
  • 著者名/発表者名: Shibata H, Mori T, Du W, Chuma M, Gotoh M, Shimazu M, Ueda M, Hirohashi S, Sakamoto M
  • 雑誌名: Ciln Cancer Res 12(18) ページ: 5363-5368
• [雑誌論文] Akt Phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular caricinoma. (2005)
  • 著者名/発表者名: Nakanishi K, Sakamoto M, Yamasaki S, Todo S, Hirohashi S
  • 雑誌名: Cancer 103 ページ: 307-312
  • 査読あり
• [雑誌論文] Multistep and multicentric development of hepatocellular carcinoma: histological analysis of 980 resected nodules. (2005)
  • 著者名/発表者名: Oikawa T, Ojima H, Yamasaki S, Takayama T, Hirohashi S, Sakamoto M
  • 雑誌名: J Hepatol 42 ページ: 225-229
  • 査読あり
• [雑誌論文] Multistep and multicentric development of hepatocellular carcinoma : histological analysis of 980 resected nodules. (2005)
  • 著者名/発表者名: Oikawa T, Ojima H, Yamasaki S, Takayama T, Hirohashi S, Sakamoto M.
  • 雑誌名: J Hepatol 42 ページ: 225-229
• [雑誌論文] Proposal of histological criteria for intraepithelial atypical/ proliferative biliary epithelial lesions of the bile duct in hepatolithiasis with respect to cholangiocarcinoma : Preliminary report based on interobserver agreement. (2005)
  • 著者名/発表者名: Yoh Z, Aishima S, Ajioka Y, Haratake J, Kage M, Kondo F, Nimura Y, Sakamoto M, Sasaki M, Shimamatsu K, Wakasa K, Young N.P, Ming F.C, Atomi Y, Nakanuma Y
  • 雑誌名: Pathol Int 55 ページ: 180-188
  • NAID: 10016474999
• [雑誌論文] Clinical and pathological significance of activation of signal trnansducer and activator of transcription 3 in prostate cancer. (2005)
  • 著者名/発表者名: Horinaga M, Okita H, Nakashima J, Kanao K, Sakamoto M, Murai M
  • 雑誌名: Urology 66 ページ: 671-675
• [雑誌論文] Domain-specific function of ShcC docking protein in neuroblastoma cells. (2005)
  • 著者名/発表者名: Miyake I, Hakomori Y, Misu Y, Nakadate H, Matsuura N, Sakamoto M, Sakai R
  • 雑誌名: Oncogene 24 ページ: 3206-3215
• [雑誌論文] Establishment of Perineural Invasion Models and Analysis of Gene Expression Revealed an Invariant Chain (CD74) as a Possible Molecule involved in Perineural Invasion in Pancreatic Cancer
  • 著者名/発表者名: Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimazu M, Hirohashi S, Nimura Y, Sakamoto M.
  • 雑誌名: Clin Cancer Res (in press)(印刷中)
• [産業財産権] 血中のCAP2の測定方法、肝臓疾患の検出方法及び血中CAP2測定用検出キット (2009)
  • 発明者名: 坂元亨宇, 他2名
  • 権利者名: 坂元亨宇, 他2名
  • 産業財産権番号: 2009-060966
  • 出願年月日: 2009-03-13
• [産業財産権] Hedgehogシグナル活性調節剤、細胞増殖調節剤及びその使用方法 (2006)
  • 発明者名: 坂元亨宇, 他2名
  • 権利者名: 坂元亨宇, 他2名
  • 産業財産権番号: 2006-317576
  • 出願年月日: 2006-11-24