The study of multistep carcinogenesis using unique animal models

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013076
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: HINO Okio Juntendo University, 医学部, 教授 (90127910)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Toshiyuki 順天堂大学, 医学部, 准教授 (40260070) ; KAJINO Kazunori 順天堂大学, 医学部, 助教 (80260066) ; MOMOSE Shuji 順天堂大学, 医学部, 准教授 (70360344)
• Project Period (FY): 2005 – 2009
• Keywords: 遺伝性がん / 癌化遺伝子 / 多段階発がん / 分子標的治療 / Niban遺伝子 / TSC遺伝子

Research Abstract

We investigated the unique animal models for the study of problems in carcinogenesis; eg., multistep carcinogenesis, cancer prevention and the development of the therapeutic treatments which can be translated into human patients. We discovered the ERC gene in Eker rat model (Tsc2 gene mutant). We developed a novel ELISA system for human asbestos-related mesothelioma. We have started a large-scale prospective study on building construction workers using our ELISA system.

Research Products

• [Journal Article] Serine 62 is phosphorylation site in folliculin, the Birt-Hogg-Dube gene product. (2010)
  • Author(s): Wang L., Kobayashi T., Piao X., Shiono M., Takagi Y., Mineki R., Taka H., Zhang D., Abe M., Son G., Hagiwara Y., Okimoto K., Matsumoto I., Kouchi M., Hino O.
  • Journal Title: FEBS Letters 584 Pages: 39-43
• [Journal Article] Frequent expression of Niban in head and neck squamous cell carcinoma and squamous dysplasia. (2010)
  • Author(s): Ito S., Fujii H., Matsumoto T., Abe M., Ikeda K., Hino O.
  • Journal Title: Head Neck 32 Pages: 96-103
• [Journal Article] Phosphorylated hamartin-Hsp70 complex regulates apoptosis via mitochondrial localization. (2010)
  • Author(s): Inoue H., Uyama T., Suzuki T., Kazami M., Hino O., Kobayashi T., Kobayashi K., Tadokoro T.
  • Journal Title: Biochem. Biophys. Res. Commun. 391 Pages: 1148-1153
• [Journal Article] Age dependence of radiation-induced renal cell carcinomas in an Eker rat model. (2010)
  • Author(s): Kokubo T., Kakinuma S., Kobayashi T., Watanabe F., Iritani R., Tateno K., Nishimura M., Nishikawa T., Hino O., Shimada Y.
  • Journal Title: Cancer Sci. 101 Pages: 616-623
• [Journal Article] Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo. (2010)
  • Author(s): Inami K., Abe M., Takeda K., Hagiwara Y., Maeda M., Segawa T., Suyama M., Watanabe S., Hino O.
  • Journal Title: Cancer Sci. 101 Pages: 969-974
• [Journal Article] Establishment of novel monoclonal antibody to human ERC/mesothelin useful for study and diagnosis of ERC/mesothelin-expressing cancers. (2009)
  • Author(s): Ishikawa K., Segawa T., Hagiwara Y., Maeda M., Abe M., Hino O.
  • Journal Title: Pathol. Int. 59 Pages: 161-166
• [Journal Article] Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway. (2009)
  • Author(s): Piao X., Kobayashi T., Wang L., Shiono M., Takagi Y., Sun G., Abe M., Hagiwara Y., Zhang D., Okimoto K., Kouchi M., Matsumoto I., Hino O.
  • Journal Title: Biochem. Biophys. Res. Commun. 389 Pages: 16-21
• [Journal Article] Establishment and chracterization of renal carcinoma cell lines from a Bhd gene mutant (Nihon) rat. (2009)
  • Author(s): Matsumoto I., Kouchi M., Okimoto K., Kijima K., Ueda T., Hirayama Y., Inoue T., Hino O.
  • Journal Title: Tumor Biology 30 Pages: 249-256
• [Journal Article] An animal model of precilinical diagnosis of pancreatic ductal carcinomas. (2009)
  • Author(s): Fukamachi K., Tanaka H., Hagiwara Y., Ohara H., Joh T., Iigo M., Alexander D.B., Xu J., Long N., Takigahira M., Yonagihara K., Hino O., Saito I.
  • Journal Title: Biochem. Biophys. Res. Commun. 390 Pages: 636-641
• [Journal Article] Tuberous sclerosis complex 2 loss-of-function mutation regulates reactive oxygen species production through Racl activation. (2008)
  • Author(s): Suzuki T., Das S.K., Inoue H., Kazami M., Hino O., Kobayashi T., Yeung R.S., Kobayashi K., Tadokoro T., Yamamoto Y.
  • Journal Title: Biochem. Biophys. Res. Commun 368 Pages: 132-137
• [Journal Article] Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma. (2008)
  • Author(s): Shiomi K., Hagiwara Y., Sonoue K., Segawa T., Miyashita K., Maeda M., Izumi H., Masuda K., Hirabayashi M., Moroboshi T., Yoshiyama T., Ishida A., Natori Y., Inoue A., Kobayashi M., Sakao Y., Miyamoto H., Takahashi K., Hino O.
  • Journal Title: Clinical Cancer Res. 14 Pages: 1431-1437
• [Journal Article] Mesomark kit detects C-ERC/mesothelin, but not SMRP with C-terminus. (2008)
  • Author(s): Segawa T., Hagiwara Y., Ishikawa K., Aoki N., Maeda M., Shiomi K., Hino O.
  • Journal Title: BBRC 369 Pages: 915-918
• [Journal Article] Diagnostic tumor marker of asbestos-related messoth. (2008)
  • Author(s): Hino O., Maeda, M.
  • Journal Title: Environmental Health and Preventive Medicine 13 Pages: 71-74
• [Journal Article] siRNA-mediated Erc gene silencing suppresses tumor growth in Tsc2 mutant renal carcinoma model. (2008)
  • Author(s): Imamura O., Okada H., Takashima Y., Zhang D., Kobayashi T., Hino O.
  • Journal Title: Cancer Letters 268 Pages: 278-285
• [Journal Article] Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnipl-like (FnipL/Fnip2) protein. (2008)
  • Author(s): Takagi Y., Kobayashi, T., Shiono M., Wang L., Piao X., Sun G., Zhang D., Abe M., Hagiwara Y., Takahashi K., Hino O.
  • Journal Title: Oncogene 27 Pages: 5339-5347
• [Journal Article] Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma. (2008)
  • Author(s): Inami K., Kajino K., Abe M., Hgiwara Y., Maeda M., Suyama M., Watanabe S., Hino O.
  • Journal Title: Oncology Reports 20 Pages: 1375-1380
• [Journal Article] Establishment of a Novel Specific ELISA system for rat N- and C-ERC/Mesothelin. -Rat ERC/Mesothelin in the body fluids of mice bearing mesothelioma-. (2008)
  • Author(s): Hagiwara Y., Hamada Y., Kuwahara M., Maeda M., Segawa T., Ishikawa K., Hino O.
  • Journal Title: Cancer Sci. 99 Pages: 666-670
• [Journal Article] Biphasic response of pancreatic β cell mass to ablation of TSC2 mice. (2008)
  • Author(s): Shigeyama Y., Kobayashi T., Kido Y., Hashimoto N., Asahara S., Matsuda T., Takeda A., Inoue T., Shibutani Y., Koyanagi M., Uchida T., Inoue M., Hino O., Kasuga M., Noda T.
  • Journal Title: Mol. Cell. Biology 28 Pages: 2971-2979
• [Journal Article] The G1556S-type tuberin variant suppresses tumor formation in tuberous sclerosis 2 mutant (Eker) rats despite its deficiency in mTOR inhibition. (2008)
  • Author(s): Shiono M., Kobayashi T., Takahashi R., Sun G., Abe M., Zhang D., Wang L., Piao X., Takagi Y., Mineki R., Taka H., Tada N., Sonobe S., Momose S., Ueda M., Hino O.
  • Journal Title: Oncogene 27 Pages: 6690-6697
• [Journal Article] ERC/mesothelin as a marker for chemotherapeutic response in patients with mesothelioma. (2008)
  • Author(s): Tajima K., Hirama M., Shiomi K, Ishiwata T., Yoshioka M., Iwase A., Iwakami S., Yamazaki M., Toba M., Tobino K., Sugano K., Ichikawa M., Hagiwara Y., Takahashi K., Hino O.
  • Journal Title: Anticancer Research 28 Pages: 3933-3936
• [Journal Article] GADD34 inhibits mammalian target of repamycin signaling via tuberous sclerosis complex and controls cell surbival under bioenergetic stress. (2007)
  • Author(s): Watanabe R., Tambe Y., Inoue H., Isono T., Haneda M., Isobe K., Kobayashi T., Hino O., Okabe H., Chano T.
  • Journal Title: Int. J. Molecular Medicine 19 Pages: 475-483
• [Journal Article] N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo N-terminal hamartin-binding and C-termin. (2007)
  • Author(s): Momose S., Kobayashi T., Tada N., Itoyama S., Hino O.
  • Journal Title: Biochem. Biophys. Res. Commun 356 Pages: 693-698
• [Journal Article] The endoplasmic reticulum stress-inducible protein Niban regulates eIF2 α and S6K1/4E-BP1 phosphorylation. (2007)
  • Author(s): Sun G.D., Kobayashi T., Abe M., Tada N., Adachi H., Shiota A., Totsuka Y., Hino O.
  • Journal Title: Biochem. Biophys. Res. Commun 360 Pages: 181-187
• [Journal Article] Birt-Hogg-Dube (BHD) gene mutations in human gastric cancer with high hrequency microsatellite instability. (2007)
  • Author(s): Jiang W., Fujii H., Matsumoto T., Ohtsuji N., Tsurumaru M., Hino O.
  • Journal Title: Cancer Letter 248 Pages: 103-111
• [Journal Article] Establishment of the ELISA system to detect the amino terminal secretory form of rat Erc/ Mesothelin. (2007)
  • Author(s): Nakaishi M., Kajino K., Ikesue M., Hagiwara Y., Kuwahara M., Mitani H., Horikoshi Y., Segawa T., Kon S., Maeda M., Baiyin T., Abe M., Yokoyama M., Hino O.
  • Journal Title: Cancer Sci. 98 Pages: 659-664
• [Journal Article] A diagnostic biomarker of Asbestos-related mesothelioma-Example of translational research-. (2007)
  • Author(s): Hino O., Shiomi K., Maeda M.
  • Journal Title: Cancer Sci. 98 Pages: 1147-1157
• [Journal Article] Suppression of viral replication by stress-inducible GADD34 protein via the mammalian serine/threonine protein kinase mTOR pathway. (2007)
  • Author(s): Minami K., Tambe Y., Watanabe R., Isono T., Haneda M., Isobe K., Kobayashi T., Hino O., Okabe H., Chano T., Inoue H.
  • Journal Title: J. Virology 81 Pages: 11106-11115
• [Journal Article] Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene. (2006)
  • Author(s): Togashi Y, Kobayashi T, Momose S, Ueda M, Okimoto K, Hino O
  • Journal Title: Oncogene 25 Pages: 2885-2889
• [Journal Article] Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt-Hogg-Dube syndrome. (2006)
  • Author(s): Kouchi M., Okimoto K., Matsumoto I., Tanaka K., Yasuba M., Hino O.
  • Journal Title: Virchow Archives 448 Pages: 463-471
• [Journal Article] Novel ELISA system for detection of "N-ERC/mesothelin" in the sera of mesothelioma patients. (2006)
  • Author(s): Shiomi K., Miyamoto H., Segawa T., Hagiwara Y., Ota A., Maeda M., Takahashi K., Masuda K., Sakao Y., Hino O.
  • Journal Title: Cancer Sci 97 Pages: 928-932
• [Journal Article] A novel tumor marker, Niban, is expressed in subsets of thyroid tumors and Hashimoto's thyroiditis. (2006)
  • Author(s): Matsumoto F., Fujii H., Abe M., Kajino K., Kobayashi T., Matsumoto T., Ikeda K., Hino O.
  • Journal Title: Human Pathology 37 Pages: 1592-1600
• [Journal Article] Neuromuscular abundance of RB1CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation. (2006)
  • Author(s): Chano T., Saji M., Inoue H., Minami K., Kobayashi T., Hino O., Okabe H.
  • Journal Title: Int. J. Molecular Medicine 18 Pages: 425-432
• [Journal Article] Intraction of Fox01 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. (2006)
  • Author(s): Cao Y., Kamioka Y., Yokoi N., Kobayashi T., Hino O., Onodera M., Mochizuki N., Nakae J.
  • Journal Title: J. Biological Chemistry 281 Pages: 40242-40251
• [Journal Article] Blood tests for Asbestos-related mesothelioma. (2006)
  • Author(s): Maeda M., Hino O.
  • Journal Title: Oncology 71 Pages: 26-31
• [Journal Article] A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. (2005)
  • Author(s): Ishii T., Yasuda K., Akatsuka A., Hino O., Hartman P.S., Ishii N.
  • Journal Title: Cancer Res 65 Pages: 203-209
• [Journal Article] Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor. (2005)
  • Author(s): Ma L., Teruya-Feldstein J., Behrendt N., Chen Z., Noda T., Hino O., Cordon-Cardo C., Pandolfi P.P.
  • Journal Title: Genes & Development 19 Pages: 1779-1986
• [Journal Article] Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.
  • Author(s): Kunogi M., Kurihara M., Shigihara-Ikegami T., Kobayashi T., Shindo N., Kumasaka T., Gunji Y., Kikkawa M., Iwakami S., Hino O., Takahashi K., Seyama K.
  • Journal Title: J. Med. Genetics (in press)
• [Journal Article] Development of positron emission tomography imaging by 64Cu-labeled Fab for detecting ERC/mesothelin in mesothelioma mouse model.
  • Author(s): Yoshida C., Sogawa C., Tsuji A., Sudo H., Sugyo A., Uehara T., Hino O., Yoshii Y., Fujibayashi Y., Fukumura T., Koizumi M., Arano Y., Saga T.
  • Journal Title: Nuclear Medicine Communications (in press)
• [Patent(Industrial Property Rights)] 中皮種診断剤、中皮種診断キットおよび中皮種診断方法
  • Inventor(s): 樋野興夫、清藤勉
  • Industrial Property Rights Holder: 株式会社免疫生物研究所
  • Industrial Property Number: 特許出願 PCT/JP2007/001373(出願日:2007/12/7), 特願2006-331409(2006/12/8)