2007 Fiscal Year Final Research Report Summary
Molecular mechanisms of associations between abnormal differentiation and altered regulations of gene expressions.
| Project/Area Number |
18590308
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
OSADA Hirotaka Aichi Cancer Center Research Institute, Division of Molecular Oncology, Section Head (30204176)
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| Project Period (FY) |
2006 – 2007
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| Keywords | lung cancer / neuroendocrine / epigenetic / miRNA / histone modification / chromatin |
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| 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
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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. Less
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Research Products
(46 results)
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[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
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Journal Title
Oncogene 26
Pages: 6099-6105
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Int J Cancer. 120
Pages: 543-51
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of c.ancer2007
Author(s)
Ebi, H., Matsuo, K., Sugito, N., Suzuki, M., Osada. H., Tajima, K., Ueda, R. and Takahashi, Ta.
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Journal Title
Cancer Res 67
Pages: 11158-11165
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
Hepatol Res 37
Pages: 974-983
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
Cancer Res 67
Pages: 6007-6011
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
Cancer Sci 97
Pages: 753-9
Description
「研究成果報告書概要(欧文)」より
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[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
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