Isolation of genomic instability genes that are associated with malignancy

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: SUZUKI Motoshi Nagoya University, 大学院・医学系研究科, 講師 (80236017)
• Co-Investigator(Kenkyū-buntansha): MURATE Takashi 名古屋大学, 医学部, 教授 (30239537)
• Project Period (FY): 2008 – 2010
• Keywords: DNA複製 / ゲノムインスタビリティー / 癌 / DNA修復 / 細胞周期

Research Abstract

In examinations of 158 lung cancers and 5 mixtures of 10 normal lungs, cell cycle- and checkpoint-related genes generally showed mRNA expression increases in cancer, whereas POLD4 showed reduced mRNA in small cell lung cancer (SCLC). In the absence of POLD4, we observed defect in DNA repair activity, delay in cell cycle, and increased frequency of chromosomal break induction. Overexpression of an engineered POLD4 carrying silent mutations at the siRNA target site rescued these phenotypes, firmly establishing the role of POLD4 in these effects. In order to identify gene products that interact with POLD4, we performed an MS analysis using the immunoprecipitated protein fractions with POLD4, where ATM, CDC14 and other cell cycle checkpoint/progression proteins were detected. We further identified novel single nucleotide variations (SNV) in lung cancer cell lines. One of the SNV reduced the physical interaction ability with the catalytic subunit of pol delta. These results suggest that the newly identified SNV could be involved in the carcinogenesis by modifying DNA replication ability of DNA polymerase delta.

Research Products

• [Journal Article] Proteasomal Non-catalytic Subunit PSMD2 as a Potential Therapeutic 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. in press.
• [Journal Article] がんとmicroRNA癌細胞イラストレーテッド (2011)
  • Author(s): 鈴木元、高橋隆
  • Journal Title: (印刷中)
• [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. 1811 Pages: 119-128
• [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 別冊号 Pages: 86-90
• [Journal Article] がんとmicroRNA血液・腫瘍科 (2010)
  • Author(s): 鈴木元、高橋隆
  • Journal Title: 61 Pages: 621-626
• [Journal Article] Mechanism of increased PLD1 gene expression during early adipocyte differentiation process of mouse cell line 3T3-L1. (2010)
  • Author(s): Gao S, Ito H, Murakami M, Yoshida K, Tagawa Y, Hagiwara K, Takagi A, Kojima T, Suzuki M, Banno Y, Ohguchi K, Nozawa Y, Murate T.
  • Journal Title: J Cell Biochem. 109 Pages: 375-382
• [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, Akashi T, Masuda Y, Kamiya K, Takahashi T, Suzuki M.
  • Journal Title: Biochem Biophys Res Commun. 391 Pages: 542-546
• [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. 70 Pages: 8407-8416
• [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, Ito H, Hagiwara K, Yoshida K, Sobue S, Ichihara M, Takagi A, Kojima T, Tanaka K, Tamiya-Koizumi K, Kyogashima M, Suzuki M, Banno Y, Nozawa Y, Murate T.
  • Journal Title: J Neurochem. 112 Pages: 511-520
• [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). 9 Pages: 534-541
• [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
• [Journal Article] Counterbalance between RB inactivation and miR-17-92 overexpression in reactive oxygen species and DNA damage induction in lung cancers. (2009)
  • Author(s): Ebi H, Sato T, Sugito N, Hosono Y, Yatabe Y, Matsuyama Y, Yamaguchi T, Osada H, Suzuki M, Takahashi T.
  • Journal Title: Oncogene. 28 Pages: 3371-3379
• [Journal Article] p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation. (2009)
  • Author(s): Furuhata A, Kimura A, Shide K, Shimoda K, Murakami M, Ito H, Gao S, Yoshida K, Tagawa Y, Hagiwara K, Takagi A, Kojima T, Suzuki M, Abe A, Naoe T, Murate T.
  • Journal Title: Biochem Biophys Res Commun. 383 Pages: 411-416
• [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, Murakami M, Ito H, Gao S, Yoshida K, Sobue S, Kikuchi R, Iwasaki T, Takagi A, Kojima T, Suzuki M, Abe A, Naoe T, Murate T.
  • Journal Title: Leukemia. 23 Pages: 1270-1277
• [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, Murakami S, Ito S, Furuhata A, Yoshida K, Tagawa Y, Hagiwara K, Takagi A, Kojima T, Suzuki M, Banno Y, Nozawa K, Murate T.
  • Journal Title: Nagoya J Med Sci. 71 Pages: 127-136
• [Journal Article] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. (2009)
  • Author(s): Ito H, Murakami M, Furuhata A, Gao S, Yoshida K, Sobue S, Hagiwara K, Takagi A, Kojima T, Suzuki M, Banno Y, Tanaka K, Tamiya-Koizumi K, Kyogashima M, Nozawa Y, Murate T.
  • Journal Title: Biochim Biophys Acta. 1789 Pages: 681-690
• [Journal Article] PCNA mono-ubiquitination and activation of translesion DNA polymerases by DNA polymerase alpha. (2009)
  • Author(s): Suzuki M, Niimi A, Limsirichaikul S, Tomida S, Huang Q, 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
• [Journal Article] Characterization of myelodysplastic syndrome and aplastic anemia by immunostaining of p53 and hemoglobin F and karyotype analysis : differential diagnosis between refractory anemia and aplastic anemia. (2008)
  • Author(s): Iwasaki T, Murakami M, Sugisaki C, Sobue S, Ohashi H, Asano H, Suzuki M, Nakamura S, Ito M, Murate T.
  • Journal Title: Pathol Int. 58 Pages: 353-360
• [Journal Article] v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization : alteration of AU-rich element-binding proteins. (2008)
  • Author(s): Sobue S, Murakami M, Banno Y, Ito H, Kimura A, Gao S, Furuhata A, Takagi A, Kojima T, Suzuki M, Nozawa Y, Murate T.
  • Journal Title: Oncogene. 27 Pages: 6023-6033
• [Journal Article] Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat : relevance as a marker for daunorubicin sensitivity of leukemia cells. (2008)
  • Author(s): Sobue S, Nemoto S, Murakami M, Ito H, Kimura A, Gao S, Furuhata A, Takagi A, Kojima T, Nakamura M, Ito Y, Suzuki M, Banno Y, Nozawa Y, Murate T.
  • Journal Title: Int J Hematol. 87 Pages: 266-275
• [Journal Article] Hyper-phosphorylated retinoblastoma protein suppresses telomere elongation. (2008)
  • Author(s): Takemura M, Sugimura K, Okumura K, Limsirichaikul S, Suzuki M, Yamada Y, Yoshida S.
  • Journal Title: Biosci Biotechnol Biochem. 72 Pages: 630-635
• [Journal Article] let-7 regulates Dicer expression and constitutes a negative feedback loop. (2008)
  • Author(s): Tokumaru S, Suzuki M, Yamada H, Nagino M, Takahashi T.
  • Journal Title: Carcinogenesis. 29 Pages: 2073-2077
• [Presentation] ALTERATION OF LIPID CONSTITUENT IN CANCER CELL MEMBRANE 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: 20110200
• [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: 20101200
• [Presentation] ALTERATION OF LIPID CONSTITUENT IN CANCER CELL MEMBRANE 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: 20101200
• [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: 20101000
• [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: 20101000
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer. (2010)
  • Author(s): Huang QM, Tomida S, Masuda S, Arima C, Kasahara T, Osada H, Akashi T, Murate T, Kamiya K, Takahashi T, Suzuki M
  • Organizer: International Conference on Radiation and Cancer Biology at Nagasaki 2010'
  • Place of Presentation: Nagasaki
  • Year and Date: 20100200
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer. (2009)
  • Author(s): Huang QM, Tomida S, Masuda S, Arima C, Kasahara T, Osada H, Akashi T, Murate T, Kamiya K, Takahashi T, Suzuki M
  • Organizer: The 3rd International Symposium on "Molecular Science of Fluctuations toward Biological Functions"
  • Place of Presentation: Nagoya
  • Year and Date: 20091200
• [Presentation] Gene profiling listed a genomic instability gene involved in lung cancer. (2009)
  • Author(s): Suzuki M
  • Organizer: the 25th RBC International Symposium
  • Place of Presentation: Kyoto
  • Year and Date: 20091100
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer. (2009)
  • Author(s): Huang QM, Tomida S, Masuda S, Arima C, Kasahara T, Osada H, Akashi T, Murate T, Kamiya K, Takahashi T, Suzuki M
  • Organizer: The 2nd International Symposium of Nagoya Univ GCOE
  • Place of Presentation: Nagoya
  • Year and Date: 20091100
• [Presentation] Elucidation of Proteasomal Non-catalytic Subunit PSMD2 as Potential Therapeutic Target and Its Co-upregulation with Proteasome Pathway Genes in Association with Various Clinicopathologic Features in Lung Adenocarcinomas. (2009)
  • Author(s): Matsuyama M, Suzuki M, Arima C, Huang QM, Tomida S, Takeuchi T, Sugiyama R, Itoh Y, Yatabe Y, Goto H, Takahashi T
  • Organizer: The 2nd International Symposium of Nagoya Univ GCOE
  • Place of Presentation: Nagoya
  • Year and Date: 20091100
• [Presentation] Epigenetic reduction of POLD4/p12 and genomic instability induction in small cell lung cancer. (2009)
  • Author(s): Huang QM, Tomida S, Masuda S, Arima C, Kasahara T, Osada H, Akashi T, Murate T, Kamiya K, Takahashi T, Suzuki M
  • Organizer: The 19th International Symposium of Hiroshima Cancer Seminar in conjugation with Three Universities' Consortium
  • Place of Presentation: Hiroshima(Best Poster Award)
  • Year and Date: 20091100
• [Presentation] Genomic instability and aberrant fork structures induced by DNA replication errors. (2008)
  • Author(s): Suzuki M, Tanaka S, Tomida S, Murate T, Takahashi T
  • Organizer: 第67回日本癌学会学術総会、ワークショップ
  • Place of Presentation: 名古屋
  • Year and Date: 20081000
• [Presentation] let-7 regulates Dicer expression and constitutes a negative feedback loop (2008)
  • Author(s): Shogo Tokumaru, Motoshi Suzuki, Hideki Yamada, Masato Nagino, Takashi Takahashi
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 20081000
• [Presentation] PCNA Mono-ubiquitination and Activation of Translesion DNA Polymerases Caused by DNA Replication Errors. (2008)
  • Author(s): Suzuki M
  • Organizer: The 5th Forum on Oxidative Stress and Aging.
  • Place of Presentation: Ancona, Italy
  • Year and Date: 20080900
• [Remarks] ホームページ等
• [Patent(Industrial Property Rights)] Thermostable polymerases having altered fidelity and method of identifying and using same (2009)
  • Inventor(s): Loeb LA, Hood L, Suzuki M
  • Industrial Property Rights Holder: Washington University School of Medicine
  • Industrial Property Number: US patent application,20090004656
  • Filing Date: 2009-01-01