Molecular mechanisms of associations between abnormal differentiation and altered regulations of gene expressions.

• Project/Area Number: 18590308
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: OSADA Hirotaka Aichi Cancer Center Research Institute, Division of Molecular Oncology, Section Head (30204176)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,820,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: lung cancer / neuroendocrine / epigenetic / miRNA / histone modification / chromatin / 肺癌 / microRNA

Research Abstract

The proneural basic-helix-loop-helix protein achaete-scute homologue 1(ASH1) is expressed in a very limited spectrum in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features. In the present study, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/β-catenin signaling, E-cadherin, and integrinβ1 through ASH 1-mediated deacetylation and repressive trimethylation of lysine 27(H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.
We previously reported the amplification and overexpression of the miR-17-92 microRNAs(miRNA) cluster at 13q31.3 in lung cancers. In the present study, we show that inhibition of miR-17-5p and miR-20a with antisense oligonucleotides can induce apoptosis selectively in lung cancer cells overexpressing miR-17-92, suggesting the possibility of 'OncomiR addiction' to expression of these miRNAs in a subset of lung cancers. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 3' to miR-17-92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA-dependent protein kinase activation. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR-17-92, which might ultimately lead to the future translation into clinical applications.

Research Products

• [Journal Article] Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer (2008)
  • Author(s): Osada H, et. al.
  • Journal Title: Cancer Research 68 Pages: 1647-55
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lune 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: 1647-55
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MicroRNAs in Biological and Carcinogenic Processes. (2007)
  • Author(s): Osada H, et. al.
  • Journal Title: Carcinogenesis 28 Pages: 2-12
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. (2007)
  • Author(s): Nagai H, et. al.
  • Journal Title: Oncogene 26 Pages: 4025-31
  • Description: 「研究成果報告書概要(和文)」より
  • 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, et. al.
  • Journal Title: Oncogene 26 Pages: 4600-8
  • Description: 「研究成果報告書概要(和文)」より
  • 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, et. al.
  • Journal Title: Oncogene 26 Pages: 6099-6105
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. (2007)
  • Author(s): Sato N, et. al.
  • Journal Title: Int.J.Cancer 120 Pages: 543-551
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Human DREF regulates cell proliferation and ribosomal protein genes. (2007)
  • Author(s): Yamashita D, et. al.
  • Journal Title: Mol.Cell.Biol 27 Pages: 2003-13
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer. (2007)
  • Author(s): Ebi H, et. al.
  • Journal Title: Cancer Research 67 Pages: 11158-65
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. (2007)
  • Author(s): Kondo Y, et. al.
  • Journal Title: Hepatol Research 37 Pages: 974-983
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. (2007)
  • Author(s): Tanaka H, et. al.
  • Journal Title: Cancer Research 67 Pages: 6007-6011
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] MicroRNAs in Biological and Carcinogenic Processes. (2007)
  • Author(s): Osada H and Takahashi T.
  • Journal Title: Carcinogenesis 28 Pages: 2-12
  • Description: 「研究成果報告書概要(欧文)」より
• [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, and Osada H.
  • Journal Title: Oncogene 26 Pages: 4025-4031
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcnptome approach. (2007)
  • Author(s): Tomida S, Yanagisawa K, Koshikawa K, Yatabe Y, Mitsudomi T, Osada H, and Takahashi T.
  • Journal Title: Oncogene 26 Pages: 4600-4608
  • Description: 「研究成果報告書概要(欧文)」より
• [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 and Takahashi T
  • Journal Title: Oncogene 26 Pages: 6099-6105
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. (2007)
  • Author(s): Sato N, Fukui T, Taniguchi T, Yokoyama T,Kondo M, Nagasaka T, Goto Y, Gao W, Ueda Y, Yokoi K, Minna JD, Osada H, Kondo Y, and Sekido Y
  • Journal Title: Int J Cancer. 120 Pages: 543-51
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human DREF regulates cell proliferation and ribosomal protein genes. (2007)
  • Author(s): Yamashita D, Sano Y, Adachi Y, Okamoto Y, Takahashi T, Osada H, Yamaguchi T, Osumi T and Hirose F
  • Journal Title: Mol. Cell. Biol 27 Pages: 2003-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of c.ancer (2007)
  • Author(s): Ebi, H., Matsuo, K., Sugito, N., Suzuki, M., Osada. H., Tajima, K., Ueda, R. and Takahashi, Ta.
  • Journal Title: Cancer Res 67 Pages: 11158-11165
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. (2007)
  • Author(s): Kondo, Y., Shen, L., Suzuki, S., Kurokawa, T., Masuko, K., Tanaka, Y., Kato, H., Mizuno, Y., Yokoe, M., Sugauchi, F., Hirashima, N., Orito, E., Osada, H., Ueda, R., Guo, Y., Chen, X., Issa, JP. and Sekido, Y.
  • Journal Title: Hepatol Res 37 Pages: 974-983
  • NAID: 10019773990
  • Description: 「研究成果報告書概要(欧文)」より
• [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., Shmiada, Y., Osada, H., Kosaka, T., Matsubara, H., Mitsudomi, T., Sekido, Y., Tammoto, M., Yatabe, Y and Takahashi Ta.
  • Journal Title: Cancer Res 67 Pages: 6007-6011
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells (2007)
  • Author(s): Nagai H, et. al.
  • Journal Title: Oncogene 26 Pages: 4025-31
  • Peer Reviewed
• [Journal Article] Human DREF regulates cell proliferation and ribosomal protein genes. (2007)
  • Author(s): Yamashita D, et. al.
  • Journal Title: Mol. Cell. Biol 27 Pages: 2003-13
  • Peer Reviewed
• [Journal Article] RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. (2007)
  • Author(s): Sato N, et. al.
  • Journal Title: Int. J. Cancer 120 Pages: 543-51
  • 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. et al.
  • Journal Title: Oncogene (in press)
• [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. et al.
  • Journal Title: Oncogene (in press)
• [Journal Article] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. (2007)
  • Author(s): Nagai H. et al.
  • Journal Title: Oncogene (in press)
• [Journal Article] hDREF regulates cell proliferation and expression of ribosomal protein genes. (2007)
  • Author(s): Yamashita D. et al.
  • Journal Title: Molecular and Cellular Biology 27・6 Pages: 2003-13
• [Journal Article] RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. (2007)
  • Author(s): Sato N.et al.
  • Journal Title: International Journal of Cancer 120・3 Pages: 543-51
• [Journal Article] MicroRNAs in biological processes and carcinogenesis. (2007)
  • Author(s): Osada H., Takahashi T.
  • Journal Title: Carcinogenesis 28・1 Pages: 2-12
• [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, et. al.
  • Journal Title: J Clin Oncol 24 Pages: 1679-1688
  • Description: 「研究成果報告書概要(和文)」より
  • 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, et. al.
  • Journal Title: Oncogene 25 Pages: 271-277
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] EGFR point mutation in non-small cell lung cancer is occasionally accompanied with second mutation or amplification. (2006)
  • Author(s): Yokoyama T, et. al.
  • Journal Title: Cancer Science 97 Pages: 753-759
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes. (2006)
  • Author(s): Chen G-Y, et. al.
  • Journal Title: Proc Natl Acad Sci USA. 103 Pages: 16894-9
  • Description: 「研究成果報告書概要(和文)」より
  • 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 and Takahashi T.
  • Journal Title: J Clin Oncol 24 Pages: 1679-1688
  • Description: 「研究成果報告書概要(欧文)」より
• [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, and Takahashi T.
  • Journal Title: Oncogene 25 Pages: 271-7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EGFR point mutation in non-small cell lung cancer is occasionally accompanied with second mutation or amplification. (2006)
  • Author(s): Yokoyama T, Kondo M, Goto Y, Fukui T, Yoshioka H, Yokoi K, Osada H, Imaizumi K, Hasegawa Y, Shimokata K, and Sekido Y.
  • Journal Title: Cancer Sci 97 Pages: 753-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes (2006)
  • Author(s): Chen G-Y, Osada H, Santamaria-Babi L-F, and Kannagi R.
  • Journal Title: Proc Natl Acad Sci U S A. 103 Pages: 16894-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes (2006)
  • Author(s): Chen G-Y et al.
  • Journal Title: Proc Natl Acad Sci U S A. 103(45) Pages: 16894-9
• [Journal Article] EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. (2006)
  • Author(s): Yokoyama T. et al.
  • Journal Title: Cancer Science 97・8 Pages: 753-9
• [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. et al.
  • Journal Title: Journal of Clinical Oncology 24・11 Pages: 1679-88
• [Journal Article] Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers. (2006)
  • Author(s): Maeno K. et al.
  • Journal Title: Oncogene 25・2 Pages: 271-7
• [Presentation] 神経内分泌分化誘導因子ASH1によるWntシグナル抑制因子DKK1の発現抑制 (2007)
  • Author(s): 長田啓隆, 他
  • Organizer: 第30回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Roles of achaete-scute homologue 1in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: 30th Annual Meeting of the Molecular Biology Society of Japan.
  • Place of Presentation: Yokohama
  • Year and Date: 2007-12-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] シンポジウム肺癌の分子生物学と治療の進歩:神経内分泌分化肺癌におけるASH1遺伝子の機能 (2007)
  • Author(s): 長田啓隆
  • Organizer: 第66回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Lung Cancer Symposium Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. (2007)
  • Author(s): Osada H.
  • Organizer: 66th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] ASH1 Gene may be a Prototypic "Lineage-Survival Oncogene" and a Specific Therapeutic Target for Lung Cancers with Neuroendocrine Features (2007)
  • Author(s): Osada H, et. al.
  • Organizer: Japanese Society of Gene Therapy The 13th Annual Meeting
  • Place of Presentation: 名古屋
  • Year and Date: 2007-06-29
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] ASH1 gene may be prototypic "lineage-survival oncogene" and specific therapeutic target for lung cancers with neuroendocrine features. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: Japanese Society of Gene Therapy The 13th Annual Meeting
  • Place of Presentation: Nagoya
  • Year and Date: 2007-06-29
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] ASH1 gene may be prototypic "lineage-survival oncogene" and specific therapeutic target for lung cancers with neuroendocrine features. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: 第13回日本遺伝子治療学会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-06-29
• [Presentation] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: AACR annual meeting
  • Place of Presentation: 米国 ロサンジェルス
  • Year and Date: 2007-04-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: AACR annual meeting
  • Place of Presentation: Los Angels, USA
  • Year and Date: 2007-04-15
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: AACR annual meeting
  • Place of Presentation: 米国
  • Year and Date: 2007-04-15
• [Presentation] The ASH1 Gene may be a Prototypic "Lineage-Survival Oncogene" and a Specific Therapeutic Target for Lung Cancers with Neuroendocrine Features. (2007)
  • Author(s): Osada H
  • Organizer: First JCA-AACR Special Joint Conference: The Latest Advances in Lung Cancer Research
  • Place of Presentation: 名古屋
  • Year and Date: 2007-03-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The ASH1 Gene may be a Prototypic "Lineage-Survival Oncogene" and a Specific the Rapeutic Target for Lung Cancers with Neuroendocrine Features. (2007)
  • Author(s): Osada H.
  • Organizer: First JCA-AACR Special Joint Conference : The Latest Advances in Lung Cancer Research : From Basic Science to Therapeutics.
  • Place of Presentation: Nagoya
  • Year and Date: 2007-03-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Role of ASH1 gene in the development of neuroendocrine lung cancer. (2007)
  • Author(s): Osada H, et. al.
  • Organizer: 4th 21st Century COE International Symposium.
  • Place of Presentation: 名古屋
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of ASH 1 gene in the development of neuroendocrine lung cancer. (2007)
  • Author(s): Osada H.
  • Organizer: 4th 21st Century COE International Symposium.
  • Place of Presentation: Nagoya
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 神経内分泌分化誘導因子ASH1によるWntシグナル抑制因子DKK1の発現抑制 (2006)
  • Author(s): 長田啓隆, 他
  • Organizer: 第65回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2006-09-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] ASH1 induces neuroendocrine differentiation and represses DKK1, an inhibitor of Wnt signaling. (2006)
  • Author(s): Osada H, Tatematsu Y, Takeuchi T, Tomida S, Yatabe Y, Mitsudomi T, Sekido Y, Takahashi T.
  • Organizer: 65th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 2006-09-28
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. (2006)
  • Author(s): Hayashita Y, et. al.
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology
  • Place of Presentation: 京都
  • Year and Date: 2006-06-19
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. (2006)
  • Author(s): Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K,Sekido Y, and Takahashi T.
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology
  • Place of Presentation: Kyoto
  • Year and Date: 2006-06-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.pref.aichi.jp/cancer-center/400/420/421/421-03.html
• [Remarks] 愛知県がんセンター研究所 分子腫瘍学部 Webページ
  • URL: http://www.pref.aichi.jp/cancer-center/400/420/421/421-03.html
• [Patent(Industrial Property Rights)] 癌の新規治療用組成物 (2006)
  • Inventor(s): 高橋隆・柳澤聖・長田啓隆
  • Industrial Property Rights Holder: 名古屋大学・愛知県
  • Filing Date: 2006-04-27
  • Description: 「研究成果報告書概要(和文)」より
  • Overseas
• [Patent(Industrial Property Rights)] 癌の新規治療用組成物 (2006)
  • Inventor(s): 高橋 隆, 柳澤 聖, 長田 啓隆
  • Industrial Property Rights Holder: 名古屋大学, 愛知県
  • Filing Date: 2006-04-27