遺伝的揺らぎと孤発癌発生機序解明のための双方向性研究

• Project Area: Molecular Science of Fluctuations toward Biological Functions
• Project/Area Number: 21107509
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Nagoya University
• Principal Investigator: 鈴木 元 名古屋大学, 医学系研究科, 講師 (80236017)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2010: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2009: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: ゲノムインスタビリティー / 肺癌 / バイオインフォーマティクス / POLD4 / DNA複製 / PSMD2 / 揺らぎ / 細胞周期 / DNA修復 / チェックポイント / マイクロアレー

Research Abstract

肺癌組織159例のMicroarray解析の結果を用いて、mRNA発現プロファイル解析を行い、ゲノムインスタビリティー抑制に関与すると考えられる遺伝子(GILC:Genomic Instability in Lung Cancer)を抽出することによって、孤発癌において、遺伝的揺らぎがどのように実際の発がんに関与しているかという医学分野への応用と展開をめざした研究を行った。GILC1/POLD4遺伝子:肺がん患者において特異的発現低下を認めた。また、発現の低い患者においては有意に予後の低下が認められた。さらに、臨床検体において染色体のアーム欠損と有意に相関しており、GILC1/POLD4遺伝子発現が肺がんの発生と悪性化に関わりがあることを示した。GILC2/PSMD2遺伝子:肺がん患者において発現増加を認め、その原因が主に染色体上相当領域の増幅であることを示した。また、より詳細な機能を調べるためにGILC1/POLD4遺伝子ノックアウトマウス作成を目指し、この遺伝子を欠損させたキメラマウスの作成を行った。GILC2/PSMD2高発現細胞においては、実験的に細胞の生存をGILC2/PSMD2発現に依存していたことより、この遺伝子が新たな抗がん剤治療の分子標的となりうることを示した。以上、臨床検体と基礎研究からの双方向性のアプローチによって遺伝的揺らぎと孤発がんとの関係を明らかにした。

Research Products

• [Journal Article] MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis (2011)
  • Author(s): Hosono Y, Yamaguchi T, Mizutani E, Yanagisawa K, Arima C, Tomida S, Shimada Y, Hiraoka M, Kato S, Yokoi K, Suzuki M, Takahashi T
  • Journal Title: EMBO J Volume: 31 Pages: 481-493
  • Peer Reviewed
• [Journal Article] Heterogeneous sphingosine-1-phosphate lyase gene expression and its regulatory mechanism in human lung cancer cell lines (2011)
  • Author(s): Ito H, Yoshida K, Murakami M, Hagiwara K, Sasaki N, Kobayashi M, Takagi A, Kojima T, Sobue S, Suzuki M, Tamiya-Koizumi K, Nakamura M, Banno Y, Nozawa Y, Murate T
  • Journal Title: Biochim Biophys Acta Volume: 1811 Pages: 119-128
  • Peer Reviewed
• [Journal Article] Proteasomal Non-catalytic Subunit PSMD2 as a Potential The rapeutic Target in Association with Various Clinicopathologic Features in Lung Adenocarcinomas (2011)
  • Author(s): Matsuyama Y, Suzuki M, Arima C, Huang Q, Tomida S, Takeuchi T, Sugiyama R, Itoh Y, Yatabe Y, Goto H, Takahashi T
  • Journal Title: Mol Carcinog Volume: 50 Pages: 301-309
  • Peer Reviewed
• [Journal Article] Regulation of DNA polymerase POLD4 influences genomic instability in lung cancer (2010)
  • Author(s): Huang QM, Tomida S, Masuda Y, Arima C, Cao K, Kasahara TA, Osada H, Yatabe Y, Akashi T, Kamiya K, Takahashi T, Suzuki M
  • Journal Title: Cancer Res Volume: 70 Pages: 8407-8416
  • Peer Reviewed
• [Journal Article] Functions of base selection step in human DNA polymerase alpha (2010)
  • Author(s): Tanaka S, Cao K, Niimi A, Limsirichaikul S, Miao HQ, Nakamura N, Murate T, Hasegawa Y, Takahashi T, Suzuki M
  • Journal Title: DNA Repair (Amst) Volume: 9 Pages: 534-541
  • Peer Reviewed
• [Journal Article] 遺伝的揺らぎと発癌機序解明にむけて (2010)
  • Author(s): 鈴木元
  • Journal Title: メディカルバイオ Volume: 10月別冊号 Pages: 86-90
• [Journal Article] がんとmicroRNA (2010)
  • Author(s): 鈴木元、高橋隆
  • Journal Title: 血液・腫瘍科 Volume: 61 Pages: 621-626
  • NAID: 40019064166
• [Journal Article] Mechanism of Increased PLD1 Gene Expression During Early Adipocyte Differentiation Process of Mouse Cell Line, 3T3-L1 (2010)
  • Author(s): Gao S., et.al
  • Journal Title: J Cell Biochem 109 Pages: 375-382
  • Peer Reviewed
• [Journal Article] ATRA inhibits ceramide kinase transcription in a human neuroblastoma cell line, SH-SY5Y cells : the role of COUP-TFI (2010)
  • Author(s): Murakami M., et.al
  • Journal Title: J Neurochem 112 Pages: 511-520
  • Peer Reviewed
• [Journal Article] Roles of POLD4, smallest subunit of DNA polymerase delta, in nuclear structures and genomic stability of human cells. (2010)
  • Author(s): Huang QM., et.al
  • Journal Title: Biochem Biophys Res Commun 391 Pages: 542-546
  • Peer Reviewed
• [Journal Article] Functions of base selection step in human DNA poly merase alpha. (2010)
  • Author(s): Tanaka S., et.al
  • Journal Title: DNA repair (in press)
  • Peer Reviewed
• [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., et.al
  • Journal Title: Mol Carcinog (in press)
  • Peer Reviewed
• [Journal Article] p^<27> deregulation by Skp2 overexpression induced by the JAK2V617 mutation (2009)
  • Author(s): Furuhata A., et.al
  • Journal Title: Biochem Biophys Res Commun 383 Pages: 411-416
  • Peer Reviewed
• [Journal Article] GATA-1 and GATA-2 binding to 3' enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines (2009)
  • Author(s): Furuhata A., at.al
  • Journal Title: Leukemia 23 Pages: 1270-1277
  • Peer Reviewed
• [Journal Article] PCNA mono-ubiquitination and activation of translesion DNA polymerases by DNA polymerase alpha (2009)
  • Author(s): Suzuki M., et.al
  • Journal Title: J Biochem 146 Pages: 13-21
  • Peer Reviewed
• [Journal Article] Mutated Ras induced PLD1 gene expression in human colon cancer cell lines and a mouse cell line of NIH3T3 (2009)
  • Author(s): Gao S., et.al
  • Journal Title: Nagoya J Med Sci 71 Pages: 127-136
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF7, induced by anti-cancer drug, daunorubicin. (2009)
  • Author(s): Ito H., et.al
  • Journal Title: Biochim Biophys Acta 1789 Pages: 681-690
  • Peer Reviewed
• [Journal Article] Counterbalance between RB inactivation and miR-17-9 2 overexpression in reactive oxygen species and DNA damage induction in lung cancers (2009)
  • Author(s): Ebi H., et.al
  • Journal Title: Oncogene 28 Pages: 3371-3379
  • Peer Reviewed
• [Journal Article] miRNAの異常と肺癌の分子病態 (2009)
  • Author(s): 細野祥之、鈴木元、高橋隆
  • Journal Title: 実験医学 27 Pages: 1218-1222
• [Presentation] ALTERATION OF LIPID CONSTITUENT IN CANCER CELL MEMBR ANE INDUCED BY HYBRID LIPOSOME (2011)
  • Author(s): Ke Cao, Keiko Tamiya-Koizumi, Kouji Tanaka, Mamoru Kyogashima, Mitsuhiro Nakamura, Yoshiko Banno, Yuji Komizua, Ryuichi Ueoka, Motoshi Suzuki
  • Organizer: 第4回ナノ・バイオメディシンシンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2011-02-22
• [Presentation] AN APPROACH TO REVEAL THE FUNCTIONAL INTERACTION BETWEEN GENETIC FLUCTUATION AND LUNG CANCER (2010)
  • Author(s): Suzuki M
  • Organizer: The 4th International Symposium on "Molecular Science of Fluctuations toward Biological Functions"
  • Place of Presentation: Otsu
  • Year and Date: 2010-12-01
• [Presentation] ALTERATION OF LIPID CONSTITUENT IN CANCER CELL MEMBR ANE INDUCED BY HYBRID LIPOSOME (2010)
  • Author(s): Cao K, Tamiya-Koizumi K, Tanaka K, Kyogashima M, Nakamura M, Banno Y, Komizu Y, Ueoka R, Suzuki M
  • Organizer: The 4th International Symposium on "Molecular Science of Fluctuations toward Biological Functions"
  • Place of Presentation: Otsu
  • Year and Date: 2010-12-01
• [Presentation] Implications of POLD4 regulation and genomic instability in small cell lung cancer (2010)
  • Author(s): Motoshi Suzuki, Shuta Tomida, Chinatsu Arima, Yuji Masuda, Kenji Kamiya, Hirotaka Osada, Yasushi Yatabe, Qin Miao Huang, Takashi Takahashi
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-24
• [Presentation] Functions of base selection step in human DNA polymerase alpha (2010)
  • Author(s): Shigeru Tanaka, Ke Cao, Huang Qin Miao, Noriko Nakamura, Yoshinori Hasegawa, Takashi Takahashi, Motoshi Suzuki
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-24
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer." (2009)
  • Author(s): Huang QM., et.al
  • Organizer: The 3^<rd> International Symposium on "Molecular Science of Fluctuations toward Biological Functions
  • Place of Presentation: Nagoya
  • Year and Date: 2009-12-20
• [Presentation] Gene profiling listed a genomic instability gene involved in lung cancer (2009)
  • Author(s): Suzuki M
  • Organizer: Bioregulation of Radiation Response : Damage Recognition, Processing and Cellular Response
  • Place of Presentation: Kyoto
  • Year and Date: 2009-12-01
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer. (2009)
  • Author(s): Huang QM., et.al
  • Organizer: The 2^<nd> International Symp Nagoya Univ GCOE
  • Place of Presentation: Nagoya
  • Year and Date: 2009-11-25
• [Presentation] Elucidation of Proteasomal Non-catalytic Subunit PSMD2 as Potential Therapeutic Target and Its Co-upregulation with Proteasome Pathway Genes in Association with Various Clinicop athologic Features in Lung Adenocarcinomas. (2009)
  • Author(s): Matsuyama M., et.al
  • Organizer: The 2^<nd> Interntional Symp Nagoya Univ GCOE
  • Place of Presentation: Nagoya
  • Year and Date: 2009-11-25
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer (2009)
  • Author(s): Huang QM., et.al
  • Organizer: The 19th International Symposium of Hiroshima Cancer Seminar in conjugation with Three Universities' Consortium
  • Place of Presentation: Hiroshima
  • Year and Date: 2009-11-01
• [Presentation] Gene profiling identified a gene involved in genetic instability in lune cancer (2009)
  • Author(s): Suzuki M, Miao HQ, Tomida S, Masuda S, Kamiya K, Osada H, Takashi T.
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Book] 癌細胞イラストレーテッド(分担、がんとmicroRNA) (2011)
  • Author(s): 鈴木元、高橋隆
  • Publisher: 羊土社