Molecular dissection of molecular pathogenesis of lung cancer towards realization of personalized medicine

2009 Fiscal Year Final Research Report

• Project/Area Number: 17015019
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagoya University
• Principal Investigator: TAKAHASHI Takashi Nagoya University, 大学院・医学系研究科, 教授 (50231395)
• Co-Investigator(Kenkyū-buntansha): YANAGISAWA Kiyoshi 名古屋大学, 高等研究院, 特任講師 (20372112) ; TOMIDA Shuta 名古屋大学, 大学院・医学系研究科, 助教 (10372111) ; YAMAGUCHI Tomoya 名古屋大学, 大学院・医学系研究科, 助教 (70452191)
• Co-Investigator(Renkei-kenkyūsha): YANAGISAWA Kiyoshi 名古屋大学, 高等研究院, 特任講師 (20372112) ; YAMAGUCHI Tomoya 名古屋大学, 大学院・医学系研究科, 助教 (70452191)
• Project Period (FY): 2005 – 2009
• Keywords: 肺がん / マイクロアレイ / プロテオミクス / マイクロRNA / バイオインフォマティクス

Research Abstract

Our multi-faceted approach towards a better understanding of lung cancer pathogenesis revealed that two major expression profile-defined subtypes exist in lung adenocarcinomas and that TTF-1 confers lineage-specific dependency in lung adenocarcinomas. In addition, we identified mRNA and protein expression signatures highly related to postoperative prognosis, while we also found relationship between deregulation of mTOR-converging signaling and poor prognosis. Finally, we reported for the first time that let-7 is reduced, while miR-17-92 is overexpressed in lung cancers, suggesting important roles of miRNA alterations in lung carcinogenesis.

Research Products

• [Journal Article] Proteasomal non-catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas (2010)
  • Author(s): Matsuyama, Y., Suzuki, M., Arima, C., Huang, Q.M., Tomida, S., Takeuchi, T., Sugiyama, R., Itoh, Y., Yatabe, Y., Goto, H., Takahashi, T.
  • Journal Title: Mol. Carcinogenesis (in press)
  • Peer Reviewed
• [Journal Article] Functions of base selection step in human DNA polymerase alpha DNA Repair (2010)
  • Author(s): Tanaka, S., Cao, K., Niimi, A., Limsirichaikul, S., Huang, Q., Nakamura, N., Murate, T., Hasegawa, Y., Takahashi, T., Suzuki M.
  • Journal Title: DNA Repair (in press)
  • Peer Reviewed
• [Journal Article] Roles of POLD4, smallest subunit of DNA polymeraseδin nuclear structures and genomic stability of human cells (2010)
  • Author(s): Huang, Q.A., Akashi, T., Matsuda, Y., Kamiya, K., Takahashi, T., Suzuki, M.
  • Journal Title: Biochem. Biophys. Res. Comm. 391 Pages: 542-546
  • Peer Reviewed
• [Journal Article] Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma (2010)
  • Author(s): Hu Q, Akatsuka S, Yamashita Y, Ohara H, Nagai H, Okazaki Y, Takahashi T,, Toyokuni S.
  • Journal Title: Lab. Invest. (in press)
  • Peer Reviewed
• [Journal Article] Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis (2009)
  • Author(s): Tomida, S., Takeuchi, T., Shimada, Y., Arima, C., Matsuo, K., Mitsudomi, T., Yatabe, Y.,, Takahashi, T.
  • Journal Title: J. Clin. Oncol. 27 Pages: 2793-2799
  • Peer Reviewed
• [Journal Article] Relationship of deregulated signaling converging onto mTOR with prognosis and classification of lung adenocarcinoma shown by two independent in silico analyses (2009)
  • Author(s): Ebi, H. *, Tomida, S., * Takeuchi, T., Arima, C., Sato, T., Mitsudomi, T., Yatabe, Y., Osada, H.,, Takahashi, T.
  • Journal Title: Cancer Res. 69 Pages: 4027-2035
  • Peer Reviewed
• [Journal Article] Counterbalancing influence of miR-17-92 overexpression on adverse effects of RB inactivation in lung cancers (2009)
  • Author(s): Ebi, H. *, Sato, T. *, Sugito, N., Hosono, Y., Suzuki, M., Yamaguchi, T., Yatabe, Y., Osada, H.,, Takahashi, T.
  • Journal Title: Oncogene 28 Pages: 3371-3379
  • Peer Reviewed
• [Journal Article] PCNA Mono-ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymeraseα (2009)
  • Author(s): Suzuki M, Niimi A, Limsirichaikul S, Tomida S, Huang QM, Izuta S, Usukura J, Itoh Y, Hishida T, Akashi T, Nakagawa Y, Kikuchi A, Pavlov Y, Murate T,, Takahashi T.
  • Journal Title: J. Biochem. 146 Pages: 13-21
  • Peer Reviewed
• [Journal Article] Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer (2009)
  • Author(s): Yazawa, T., Sato, H., Shimoyamada, H., Okudela, K., Woo, H., Tajiri, M., Ogura, T., Ogawa, N., Suzuki, T., Mitsui, H., Ishii, J., Miyata, C., Sakaeda, M., Goto, K., Kashiwagi, K., Masuda, M., Takahashi, T.,, Kitamura, H.
  • Journal Title: Am. J. Pathol. 175 Pages: 976-987
  • Peer Reviewed
• [Journal Article] Identification of HIF-1α as a novel target for miR-17-92 microRNA cluster (2008)
  • Author(s): Taguchi, A., Yanagisawa, K., Tanaka, M., Cao, K., Matsuyama, Y., Goto, H.,, Takahashi, T.
  • Journal Title: Cancer Res. 68 Pages: 5540-5545
  • Peer Reviewed
• [Journal Article] Roles of ASH1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer (2008)
  • Author(s): Osada, H., Tomida, S., Yatabe, Y., Tatematsu, Y., Takeuchi, T., Murakami, H., Kondo, Y., Sekido, Y., Takahashi, T.
  • Journal Title: Cancer Res. 68 Pages: 1647-1655
  • Peer Reviewed
• [Journal Article] Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer (2008)
  • Author(s): Yamada, H., Yanagisawa, K., Tokumaru, S., Taguchi, A., Nimura, Y., Osada, H., Nagino, M.,, Takahashi, T.
  • Journal Title: Genes, Chromosomes, Cancer. 47 Pages: 810-818
  • Peer Reviewed
• [Journal Article] Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer (2008)
  • Author(s): Yatabe, Y., Takahashi, T.,, Mitsudomi, T.
  • Journal Title: Cancer Res. 68 Pages: 2106-2111
  • Peer Reviewed
• [Journal Article] let-7 regulates Dicer expression and constitutes a negative feedback loop (2008)
  • Author(s): Tokumaru, S., Suzuki, M., Yamada, H., Nagino, N., Takahashi, T.
  • Journal Title: Carcinogenesis 29 Pages: 2073-2077
  • Peer Reviewed
• [Journal Article] Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach (2007)
  • Author(s): Tomida, S., * Yanagisawa, K., * Koshikawa, K., Yatabe, Y., Mitsudomi, T., Osada, H., Takahashi, T.
  • Journal Title: Oncogene 26 Pages: 4600-4608
  • Peer Reviewed
• [Journal Article] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells (2007)
  • Author(s): Nagai, H., Sugito, N., Matsubara, H., Tatematsu, Y., Hida, T., Sekido, Y., Nagino, M., Nimura, Y., Takahashi, T.,, Osada, H.
  • Journal Title: Oncogene 26 Pages: 4025-4031
  • Peer Reviewed
• [Journal Article] Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92 (2007)
  • Author(s): Matsubara, H. *, Takeuchi, T. *, Nishikawa, E. *, Yanagisawa, K., Hayashita, Y., Ebi, H., Yamada, H., Suzuki, M., Nagino, M., Nimura, Y., Osada, H., Takahashi, T.
  • Journal Title: Oncogene 26 Pages: 6099-6105
  • Peer Reviewed
• [Journal Article] A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer (2007)
  • Author(s): Yanagisawa, K., * Tomida, S., * Shimada, Y., Yatabe, Y., Mitsudomi, T., Takahashi, T.
  • Journal Title: J. Natl. Cancer Inst. 99 Pages: 858-867
  • Peer Reviewed
• [Journal Article] Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1 (2007)
  • Author(s): Tanaka, H., * Yanagisawa, K., * Shinjo, K., Taguchi, A., Maeno, K., Tomida, S., Shimada, Y., Osada, H., Kosaka, T., Matsubara, H., Mitsudomi, T., Sekido, Y., Tanimoto, M., Yatabe, Y.,, Takahashi, T.
  • Journal Title: Cancer Res. 67 Pages: 6007-6011
  • Peer Reviewed
• [Journal Article] Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells (2007)
  • Author(s): Ranganathan, P., Agrawal, A., Bhushan, R., Chavalmane, A.K., Kalathur, R.K.R., Takahashi, T., Kondaiah P.
  • Journal Title: BMC Genomics 8 Pages: 98
  • Peer Reviewed
• [Journal Article] Non-genomic β estrogen receptors enhance β1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells (2007)
  • Author(s): Majidi, M., Al-Wadei, H.A., Takahashi, T., Schuller H.M.
  • Journal Title: Cancer Res. 67 Pages: 6863-6871
  • Peer Reviewed
• [Journal Article] Novel NBS1 heterozygous germline mutation causing MRE11-binding domain loss predisposes to common types of cancer (2007)
  • Author(s): Ebi, H., Matsuo, K., Sugito, N., Suzuki, M., Osada, H., Tajima, K., Ueda, R.,, Takahashi, T.
  • Journal Title: Cancer Res. 67 Pages: 11158-11165
  • Peer Reviewed
• [Journal Article] MicroRNAs in Biological Processes and Carcinogenesis (2007)
  • Author(s): Osada, H., Takahashi, T.
  • Journal Title: Carcinogenesis 28 Pages: 2-12
  • Peer Reviewed
• [Journal Article] Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors (2006)
  • Author(s): Takeuchi, T., * Tomida, S., * Yatabe, Y., Kosaka, T., Osada, H., Yanagisawa, K., Mitsudomi, T.,, Takahashi, T.
  • Journal Title: J. Clin. Oncol. 24 Pages: 1679-1688
  • Peer Reviewed
• [Journal Article] Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers (2006)
  • Author(s): Maeno, K., Masuda, A., Yanagisawa, K., Konishi, H., Osada, H., Saito, T., Ueda, R.,, Takahashi, T.
  • Journal Title: Oncogene 25 Pages: 271-277
  • Peer Reviewed
• [Journal Article] Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers (2006)
  • Author(s): Ko, K., Furukawa, K., Takahashi, T., Urano, T., Sanai, Y., Nagino, M., Nimura, Y.,, Furukawa, K.
  • Journal Title: Oncogene 25 Pages: 6924-6935
  • Peer Reviewed
• [Journal Article] Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia (2006)
  • Author(s): Sato, H., Yazawa, T., Suzuki, T., Shimoyamada, H., Okudela, K., Ikeda, M., Hamada, K., Yamada-Okabe, H., Yao, M., Kubota, Y., Takahashi, T., Kamma, H., Kitamura H.
  • Journal Title: Am J Pathol. 169 Pages: 1550-1566
  • Peer Reviewed
• [Journal Article] A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation (2005)
  • Author(s): Hayashita, Y., * Osada, H., * Tatematsu, Y., Yamada, H., Yanagisawa, K., Tomida, S., Kawahara, K., Sekido, Y.,, Takahashi, T.
  • Journal Title: Cancer Res. 65 Pages: 9628-9632
  • Peer Reviewed
• [Journal Article] The ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features (2005)
  • Author(s): Osada, H., Tatematsu, Y., Yatabe, Y., Horio, Y.,, Takahashi, T.
  • Journal Title: Cancer Res. 65 Pages: 10680-10685
  • Peer Reviewed
• [Journal Article] Histone modification in the TGFβRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines (2005)
  • Author(s): Osada, H,. Tatematsu, Y., Sugito, N., Horio, Y.,, Takahashi T.
  • Journal Title: Mol. Carcinog. 44 Pages: 233-241
  • Peer Reviewed
• [Journal Article] Reduced expression of Dicer associated with poor prognosis in lung cancer patients (2005)
  • Author(s): Karube, Y., Tanaka, H., Osada, H., Tomida, S., Tatematsu, Y., Yanagisawa, K., Yatabe, Y., Takamizawa, J., Miyoshi, S., Mitsudomi, T.,, Takahashi, T.
  • Journal Title: Cancer Sci. 96 Pages: 111-115
  • Peer Reviewed
• [Journal Article] Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small cell lung cancer with postoperative recurrence (2005)
  • Author(s): Mitsudomi, T., Kosaka, T., Endoh, H., Horio, Y., Hida, T., Mori, S., Hatooka, S., Shinoda, M., Takahashi, T., Yatabe, Y.
  • Journal Title: J. Clin. Oncol. 23 Pages: 2513-2520
  • Peer Reviewed
• [Journal Article] EGFR mutation is specific for terminal respiratory unit type adenocarcinoma (2005)
  • Author(s): Yatabe, Y., Kosaka, T., Takahashi, T., Mitsudomi, T.
  • Journal Title: Am. J. Surg. Pathol. 29 Pages: 633-639
  • Peer Reviewed
• [Journal Article] Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels (2005)
  • Author(s): He, Y., Rajantie, I., Pajusola, K., Jeltsch, M., Holopainen, T., Yla-Herttuala, S., Harding, T., Jooss, K., Takahashi, T.,, Alitalo, K.
  • Journal Title: Cancer Res. 65 Pages: 4739-4746
  • Peer Reviewed
• [Journal Article] Throwing new light on lung cancer pathogenesis: updates on three recent topics (2005)
  • Author(s): Tomida, S., Yatabe, Y., Yanagisawa, K., Mitsudomi, T.,, Takahashi, T.
  • Journal Title: Cancer Sci. 96 Pages: 63-68
  • Peer Reviewed
• [Journal Article] Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time RT-PCR (2004)
  • Author(s): Endoh, H., Tomida, S., Yatabe, Y., Konishi, H., Osada, H., Tajima, K., Kuwano, H., Takahashi, T.,, Mitsudomi, T.
  • Journal Title: J. Clin. Oncol. 22 Pages: 811-819
  • Peer Reviewed
• [Journal Article] K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation (possible contribution to non-invasive expansion of lung adenocarcinoma) (2004)
  • Author(s): Okudela, K., Hayashi, H., Ito, T., Yazawa, T., Suzuki, T., Nakane, Y., Sato, H., Ishi, H., Keqin, X, Masuda, A., Takahashi, T.,, Kitamura, H.
  • Journal Title: Am. J. Pathol. 164 Pages: 91-100
  • Peer Reviewed
• [Journal Article] Maspin expression in normal lung and non-small-cell lung cancers: cellular property-associated expression under the control of promotoer DNA methylation (2004)
  • Author(s): Yatabe, Y., Mitsudomi, T.,, Takahashi T.
  • Journal Title: Oncogene 23 Pages: 4041-4049
  • Peer Reviewed
• [Journal Article] CK20 expression, CDX2 expression, K-ras mutation, and globet cell morphology in a subset of lung adenocarcinomas (2004)
  • Author(s): Yatabe, Y., Koga, T., Mitsudomi, T.,, Takahashi, T.
  • Journal Title: J. Pathol. 203 Pages: 645-652
  • Peer Reviewed
• [Journal Article] Reduced expression of class II HDAC genes are associated with poor prognosis in lung cancer patients (2004)
  • Author(s): Osada H., Tatematsu, Y., Saito, H., Yatabe, Y., Mitsudomi, T.,, Takahashi, T.
  • Journal Title: Int. J. Cancer 112 Pages: 26-32
  • Peer Reviewed
• [Journal Article] Gene expression-based, individualized outcome prediction of surgically treated lung cancer patients (2004)
  • Author(s): Tomida, S., * Koshikawa, K., * Yatabe, Y., Harano, T., Ogura, N., Mitsudomi, T., Some, M., Yanagisawa, K., Takahashi, T., Osada, H.,, Takahashi, T.
  • Journal Title: Oncogene 23 Pages: 5360-5370
  • Peer Reviewed
• [Journal Article] Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival (2004)
  • Author(s): Takamizawa, J. *, Konishi, H. *, Yanagisawa, K., Tomida, S., Osada, T., Harano, T., Yatabe, Y., Nagino, M., Nimura, Y., Mitsudomi, T.,, Takahashi, T.
  • Journal Title: Cancer Res. 64 Pages: 3753-3756
  • Peer Reviewed
• [Journal Article] Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines (2004)
  • Author(s): Nakagawa, T., Hayashita, Y., Maeno, K., Masuda, A., Sugito, N., Osada, T., Hideki, E., Yanagisawa, K., Ebi, H., Shimokata, K.,, Takahashi, T.
  • Journal Title: Cancer Res. 64 Pages: 4826-4832
  • Peer Reviewed
• [Journal Article] Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications (2004)
  • Author(s): Kosaka, T., Yatabe, Y., Endoh, H., Kuwano, H., Takahashi, T.,, Mitsudomi, T.
  • Journal Title: Cancer Res. 64 Pages: 8919-8923
  • Peer Reviewed
• [Presentation] MicroRNA alterations in the pathogenesis of lung cancers (2010)
  • Author(s): Takahashi, T.
  • Organizer: 1st AACR-IASLC Joint Conference: Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy
  • Place of Presentation: San Diego, USA
  • Year and Date: 20100111-20100114
• [Presentation] Expression profiling-based approaches for a better understanding of human lung cancer biology (2009)
  • Author(s): Takahashi, T.
  • Organizer: 13th World Conference on Lung Cancer, IASLC
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20090731-20090804
• [Presentation] Improved integrative "omics" view and an unresolved question in lung cancer pathogenesis (2008)
  • Author(s): Takahashi, T.
  • Organizer: 1st European Lung Cancer Conference
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 20080423-20080426
• [Presentation] Multidirectional dissection of the molecular pathogenesis of lung cancers (2005)
  • Author(s): Takahashi, T.
  • Organizer: The 11th World Conference on Lung Cancer - International Association for the Study of Lung Cancer
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20050702-20050707
• [Book] Biology of lung cancer.(RJ Mason, VC Broaddus JF Murray, JA Nadel,(eds.), Textbook of Respiratory Medicine., 4th edition) (2005)
  • Author(s): Takahashi T., Sidransky, D.
  • Total Pages: 1311-1327
  • Publisher: Elsevier Science
• [Remarks] 平成19年6月7付 読売新聞、日本経済新聞、中日新聞、日刊工業新聞「肺癌症例の術後予後の予測に有用な25 種類のタンパクで構成されるタンパク発現パターンの抽出に成功し、分子病態解明と個別化治療(オーダーメード医療)の実現に大きく寄与し得る結果を得た。」との内容で新聞報道された。
• [Patent(Industrial Property Rights)] 細胞増殖阻害剤 (2008)
  • Inventor(s): 高橋隆、山口知也、冨田秀太
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Number: 特許
  • Filing Date: 2008-07-18
• [Patent(Industrial Property Rights)] 肺腺癌患者の術後再発を予測するための方法及び組成物 (2007)
  • Inventor(s): 高橋隆、冨田秀太、竹内俊幸, 他
  • Industrial Property Rights Holder: 名古屋大学、(株)オンコミクス、愛知県
  • Industrial Property Number: 特許
  • Filing Date: 2007-12-28
• [Patent(Industrial Property Rights)] がん転移抑制組成物 (2006)
  • Inventor(s): 高橋隆、柳澤聖、冨田秀太, 他
  • Industrial Property Rights Holder: 名古屋大学、愛知県
  • Industrial Property Number: 特許
  • Filing Date: 2006-12-28
• [Patent(Industrial Property Rights)] がん転移抑制組成物 (2006)
  • Inventor(s): 高橋隆、柳澤聖、冨田秀太, 他
  • Industrial Property Rights Holder: 名古屋大学、愛知県
  • Industrial Property Number: 特許
  • Filing Date: 20060339