トップページ研究室紹介(附属神経疾患・腫瘍分子医学研究センター)腫瘍病態統御部門 分子腫瘍学(がん細胞)

腫瘍病態統御部門

分子腫瘍学(がん細胞)

研究室概要

 分子腫瘍学分野は、日本を始めとする先進諸国で最も多くの生命を奪っている肺癌を中心とする、いわゆる難治癌の分子病態について多角的に研究を進めています。その研究プロジェクトの内容は、癌化メカニズムに関わる基礎的な研究から、革新的な診断・治療へのトランスレーションを目指した応用研究まで多岐に渡ります。しかし、いずれの研究プロジェクトにおいても常に私たちが意識していることは、難治癌の分子病態を一つの疾患として統合的に理解し、それによって得られた成果を多くの人の生命を奪い続けている難治癌の克服につなげていくことです。もう一つ私たちの研究室を特徴づけているのは、これまで自分達に全く馴染みの無い新しい研究分野やアプローチにも、難治癌を本当に理解する上で大事だと思えば、臆せず積極果敢に取り組む攻めの姿勢です。今後は、ヒトゲノムの解読完了と網羅的解析における技術革新を追い風に、癌の分子病態を“システム”の異常として捉えることも目指していこうとしています。

独自HPへのリンク

研究プロジェクト

I) ヒト肺癌の分子病態の解明を目指して:

i) マイクロRNAの発現異常
 マイクロRNA遺伝子は蛋白に翻訳されず、~22塩基の小さなRNA分子として働き、mRNAの蛋白への翻訳を抑制します。私たちは世界に先駆けてlet-7マイクロRNAがヒトの癌の発生・進展に深く関与することを発見しました。let-7マイクロRNAの異常な発現低下が肺癌に高頻度に検出されることや、それが患者の臨床病態に関連すること、さらにはマイクロRNAに癌細胞の増殖を抑制する活性があることを初めて報告しました。また、逆に肺癌で過剰発現しているマイクロRNAを探索する中で、miR-17-92マイクロRNAクラスターが時に遺伝子増幅を伴いつつ、肺小細胞癌を中心に過剰発現しており、肺癌細胞の増殖と生存に関わっていることを見出しました。これらのマイクロRNAを中心に、マイクロRNAがどのように癌の発生と進展に関わっているのかを詳細に研究しています。また、これまで部分的な解明に成功してきたマイクロRNAとmRNAが織りなす複雑で精緻な制御ネットワークに関して、システム生物学研究者らとのスーパーコンピュータを用いた密接な共同研究を通じて、その全貌解明を目指した大規模な検討を進めようとしています。
 さて、私たちが肺癌におけるlet-7の異常について研究を始めたときには、がん研究においてマイクロRNAは全く注目されていませんでしたが、世界中で研究が進み今やlet-7は代表的な癌抑制遺伝子タイプのマイクロRNAと考えられるようになりました。新しい研究分野に果敢に挑戦する私達のスタイルを、これからも大事にしていきたいと思っています。

 

 

ii) 癌のリネッジ特異的な生存シグナル依存
 近年、特定のリネッジの細胞の分化プロセスに関与する調節因子の発現持続が、発癌プロセスにも深く関与するという新しい概念が提唱され、組織特異的な発癌メカニズムの解明に寄与するものとして注目を集めています。私達は転写因子を規定するTTF-1遺伝子が、末梢肺のリネッジ特異的な発生・分化のマスター制御因子として機能しているのみならず、その発現持続が末梢気道上皮を発生母地とする肺腺癌の生存自体にも必須であり、発癌と進展に大きく関与していることを世界に先駆けて報告しました。同様の知見は、その後米国の3つの研究グループからも相次いで報告され、肺腺癌におけるTTF-1の重要性、つまりは肺腺癌の発生と進展における役割は大きな注目を集めています。
 そこで、転写因子であるTTF-1遺伝子が、どのような下流遺伝子(群)の転写制御を通じてリネッジ特異的な肺腺癌の生存シグナルを伝えているのかという課題を中心に、TTF-1の発現持続と肺腺癌の分子病態との関連について、さまざまな角度から検討を進めています。TTF-1によって制御される下流分子の同定とその機能の全貌を明らかにすることは、難治癌の代表例たる肺腺癌の分子病態の解明のみならず、革新的な分子標的の同定と創薬開発にもつながるものと大いに期待しています。

 

 

iii) 浸潤・転移の分子機構
 がんは浸潤と転移によって人を死に至らしめます。当研究室で樹立された極めて高い血行性及びリンパ行性転移能を持つヒト肺癌細胞亜株(LNM35株)を用いた転移研究モデル系の確立に成功し、その網羅的発現解析データを基盤に癌細胞の浸潤・転移の分子機構に関する様々な研究を展開して来ました。CIMと名付けた分子は、ERに局在し微小環境の低酸素・低栄養などが惹起するERストレス応答に重要な働きを担っており、極めて有望な分子標的です。CIM分子の細胞内シグナル伝達の解明を目指し、我々が得意とするプロテオミクス解析やバイオインフォマティクス解析技術を駆使した、CIM結合分子の網羅的探索・同定や下流遺伝子群・パスウェイの同定による機能解析を進めています。同様に、私たちが癌転移関連分子として単離・同定したCLCP1遺伝子の機能についても、愛知県がんセンターの共同研究者らとともに詳細な検討を進めています。
 また、分子標的薬の創薬開発を進める上で有利なキナーゼや細胞膜受容体分子に焦点を絞った最先端のプロテオミクス解析をLNM35株に適用し、さらなる分子標的の探索・同定も進めつつあります。

 

iv) ゲノム不安定性の獲得
 ヒト肺癌における複数の細胞周期チェックポイント異常の存在を明らかとするなど、ゲノム安定性の維持機構の破綻が、ヒト癌の発生と進展において果たす役割についても研究を進めています。とくに、DNAの複製と修復を担いゲノム安定性の維持に密接に関わるDNAポリメラーゼデルタの構成分子のPOLD4が、ヒト肺小細胞癌において異常な発現低下を示すことを発見し、現在様々な観点からその肺癌の発生・進展における役割の解明を進めているところです。

 

 

II) 臨床現場へのトランスレーションを目指して:

i) ゲノミクス解析を基盤とする展開
 肺腺癌のWHO分類は多くの問題を抱えていますが、ゲノミクス解析研究を通じて発症母地リネッジと関連する2種類に大別可能なことを示した私たちの研究成果は、WHO分類改定へ向けた国際的ワーキンググループにおける検討に大きな影響を与えました。また、肺癌は難治癌の代表例であり、外科的切除が現時点で完全治癒の希望をもたらしえる唯一の治療法です。しかし、実際には早期のI期症例の約30%は術後に再発しますが、その予測は極めて困難です。私たちは、肺癌腫瘍組織の網羅的な遺伝子発現解析データに対して、綿密なバイオインフォマティクス解析を加えることによって、I期症例の中においてさえも極めて高精度に術後再発が90%近くにも及ぶ極度のハイリスク群を同定可能な、発現シグネチャーの同定と予後予測判別モデルの構築に成功しました。転移巣が極めて微少なうちにテーラーメイドに強力な術後治療を加えることで、大幅な再発の抑制と生存率の改善が期待されます。現在、広く臨床応用するための研究開発を産学連携によって進めています。また、最新のバイオインフォマティクス解析手法の応用によって、肺癌の外科手術後に再発・死亡に至った患者さんの癌細胞には、mTORに集約するパスウェイが劣悪な微小環境への適応につながる脱統御を示すことも明らかとしています。
 現在、mRNAのトランスクリプトームのみならず、マイクロRNAを含むノンコーディングRNAのトランスクリプトーム解析を進めており、がんの分子或いは臨床病態との関連性について多角的に検討を加えて、より良く肺癌の個性を描出し、さらに高精度な再発・死亡の予測や薬剤感受性予測を実現して行きたいと考えています。

 

 

ii) プロテオミクス解析を基盤とする展開
 プロテオミクス解析では、ゲノム情報の最終産物であるタンパク質を直接解析します。癌の発生・進展に関わる蛋白や、早期発見や薬剤感受性予測に有用なマーカー蛋白群の網羅的な探索・同定に大きく貢献することが期待されています。しかしながら、とくにプロテオミクス技術の臨床応用は依然として発展途上にあり、世界的に見ても臨床プロテオミクス研究の主要な成果も限られています。私たちは、蛋白発現シグネチャーに基づく肺癌診断法や、さらには早期の肺癌の外科手術後の再発・死亡の高精度な予測においてパイオニアとしての実績を有します。この成果の臨床への導入は、現行のCTなどの画像検査では検出不可能な再発の元となる微小な転移が残存する症例を高精度に同定し、強力な術後治療によって、肺癌の治癒率の向上をもたらす可能性があると期待されます。
 また、肺癌以上の難治癌の膵癌は早期診断が依然として極めて難しく、生存率はこの10年間に殆ど改善していません。私たちは血漿を用いた膵癌のプロテオミクス診断法の開発にも成功しています。外科切除で治癒を期待できるほど早期に発見される症例の割合が向上すれば、死亡率の低減が達成されるものと期待されます。今後はさらに難治癌を中心として、それぞれの患者さんに個別的な治療方針の決定に有用な情報となる、薬剤感受性や副作用の予測を可能とする蛋白発現シグネチャー同定などを通じて、革新的な診断法の開発に貢献していきたいと考えています。
 もちろん、プロテオミクス技術の発展は基礎研究分野の推進に大きな成果を上げつつありますが、我々も蛋白の同位体標識技術を応用した網羅的なプロテオミクス解析をマイクロRNA研究に初めて応用するなど、多角的に進めつつあるヒトがんの発生・進展に関わる分子病態の解明を目指した研究に、我々の技術的な優位性を生かした応用を展開しつつあります。

 

 

構成員名/英名表記 役職 所属
高橋 隆/TAKAHASHI Takashi
教授分子腫瘍学
鈴木 元/SUZUKI Motoshi
講師分子腫瘍学
柳澤 聖/YANAGISAWA Kiyoshi
特任講師(高等研究院テニュアトラックプログラム)分子腫瘍学
山口知也/YAMAGUCHI Tomoya
助教分子腫瘍学
有馬千夏/ARIMA Chinatu
特任助教 (GCOEプログラム)分子腫瘍学

志望される方へ

大学院生(博士・修士)

 私たちの分子腫瘍学分野で進められつつある研究は、「がん」の本態解明を目指した基礎的な研究から、ヒトがんの克服を目指したトランスレーショナルな研究に至るまで多岐に渡ります。私自身(高橋)は、外科医としての修練を経て基礎研究に転身しましたが、当分野のスタッフ達はMDとPhD、ウェット系とドライ系或いは、同じMDでもスタートが内科、外科、基礎と、実に多様なバックグラウンドを持ちます。そして、私たちはそれぞれの特性を発揮しつつ、互いの密接な協力体制の下に多彩な研究を進めつつあります。
 したがって、大学院生はそのようなスタッフたちとのインタラクションの中で、科学的な課題に対する多角的な見方や発想法の習得の機会をふんだんに得ることができます。また、研究内容も極めて基礎的な内容から、ゲノム情報や最新のマススペクトロメトリーを活用し先端医療としての還元を直接目指した応用研究まで多彩です。大学院生として研鑽を積む中で、医学部を卒業した方々のみならず、薬学・理学・農学などの他の学部を卒業した方々にとっても、自分の興味と特性がどのようなアプローチの医学研究にもっともフィットするのかを模索する良い機会になることと思います。また、臨床部門の医師との交流も盛んであり、「がん」診療上の課題と、基礎的或いはトランスレーショナルな研究の成果が、どのように摺り合わされ追求され得るかについても学ぶことができるでしょう。将来的にがんの医学・医療の前進に貢献したいと考えている意気軒昂な“あなた”にとって、刺激に満ちた研究室だと思います。
 博士課程の大学院生は、欧文の一流誌に論文を発表し学位を取得することを目指します。その過程で、将来あなたが研究を主導する立場になるために必要な基盤を学んで欲しいと思います。大学院生は、日常的なディスカッションや、教授らスタッフとの個別ミーティング(毎火曜日、順に月に一度程度の頻度で)、研究室全員でのプログレスリポートとジャーナルクラブ(毎金曜日、担当するのは2~3カ月に一度の頻度)を通じて、研究を進める上で必要な実験手技や文献的知識のみならず、研究の着想と組み立て方や英語論文の執筆の仕方にいたるまで、細やかな指導を受けることになります。留学の相談にも積極的に対応しており、2010年7月現在ハーバード、UCLA、フレッドハッチンソンのそれぞれに3人が留学中です。
 修士課程の大学院生達に対しては、博士課程に進んだ際に欧文の一流誌に発表できる研究を展開できるように、それに必要な基盤を涵養できるように指導しています。そのために必要な実験手技や基本的な文献的知識のみならず、研究の進め方の基本を習得しましょう。なお、修士課程の大学院生には、なるべく博士課程まで進むような人を希望します。

医学部学生

 研究に興味を持つ名大医学部の学生の中から、夏季休業期間中のサマースチューデントなどとして、ある程度まとまって参加できる人を受け入れています。スタッフらから基礎的な実験手技を最初は手取り足取り教えて貰い、だんだんとペースをつかんで来たら、あとは本人のやる気次第です。なかには、すっかりラボの一員として放課後とか週末にも頑張って、共同筆頭著者として論文にまとめ上げた人たちさえいますが、逆に一夏で脱落するのも良い経験になるかも知れません。
 なお、研究に賭けているスタッフたちが彼らの時間を割いてチャンスを与えてくれていることを理解できる人は大歓迎ですが、きちんと対応したいので基本的に各学年2名までしか受け入れていません。興味のある方は、教授にメールしてみてください。

連絡先

高橋 隆

〒466‐8550
名古屋市昭和区鶴舞町65
名古屋大学大学院医学系研究科
附属神経疾患・腫瘍分子医学研究センター
腫瘍病態統御部門・分子腫瘍学分野
Phone: (052) 744-2454
Fax: (052) 744-2457
E-mail: tak@med.nagoya-u.ac.jp

業績(最近10年間に発表した論文)

2010

1 Matsuyama Y, Suzuki M, Arima C, Huang Q M, Tomida S, Takeuchi T, Sugiyama R, Itoh Y, Yatabe Y, Goto H, Takahashi T: Proteasomal non-catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas. Mol Carcinogenesis (in press).
2 Tanaka S, Cao K, Niimi A, Limsirichaikul S, Huang Q, Nakamura N, Murate T,
Hasegawa Y, Takahashi T, Suzuki M: Functions of base selection step in human DNA polymerase alpha. DNA Repair 9:534-541, 2010.
3 Huang QM, Akashi T, Matsuda Y, Kamiya K, Takahashi T, Suzuki M: Roles of POLD4, smallest subunit of DNA polymerase ?? in nuclear structures and genomic stability of human cells. Biochem Biophys Res Comm 391:542-546, 2010.
4 Hu Q, Akatsuka S, Yamashita Y, Ohara H, Nagai H, Okazaki Y, Takahashi T, Toyokuni S: Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. Lab. Invest. (in press)
5 Heishi T, Hosaka T, Suzuki H, Suzuki Y, Miyashita H, Oike Y, Takahashi T, Nakamura T, Arioka S, Mitsuda Y, Takakura T, Hojo K, Matsumoto M, Yamauchi C, Ohta H, Sonoda H, Sato Y. Endogenous angiogenesis inhibitor vasohibin1 exhibits a broad-spectrum anti-lymphangiogenic activity and suppresses lymph node metastasis. Am J Pathol (in press).
6 Sadej R, Romanska H, Kavanagh D, Baldwin G, Takahashi T, Kalia N, Berditchevski F. Tetraspanin CD151 regulates TGF beta signaling: implication in tumour metastasis. Cancer Res. (in press).
7 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: ATRA inhibits ceramide kinase transcription in a human neuroblastoma cell line, SH-SY5Y cells: the role of COUP-TFI. J Neurochem 112: 511-520, 2010.

 

2009

1 Tomida S, Takeuchi T, Shimada Y, Arima C, Matsuo K, Mitsudomi T, Yatabe Y, Takahashi T: Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis. J Clin Oncol 27:2793-2799, 2009.
2 Ebi H*, Tomida S,* Takeuchi T, Arima C, Sato T, Mitsudomi T, Yatabe Y, Osada H, Takahashi T: Relationship of deregulated signaling converging onto mTOR with prognosis and classification of lung adenocarcinoma shown by two independent in silico analyses. Cancer Res. 69: 4027-2035, 2009 (*equal contributors).
3 Ebi H*, Sato T*, Sugito N, Hosono Y, Suzuki M, Yamaguchi T, Yatabe Y, Osada H, Takahashi T: Counterbalancing influence of miR-17-92 overexpression on adverse effects of RB inactivation in lung cancers. Oncogene 28:3371-3379, 2009. (*equal contributors)
4 Suzuki M, Niimi A, Limsirichaikul S, Tomida S, Huang Q M, Izuta S, Usukura J, Itoh Y, Hishida T, Akashi T, Nakagawa Y, Kikuchi A, Pavlov Y, Murate T, Takahashi T: PCNA Mono-ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymerase ?? J Biochem 146: 13-21, 2009.
5 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: Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer. Am J Pathol 175: 976-987, 2009.
6 Okudera K, Yazawa T, Woo T, Sakaeda M, Ishii J, Mitsui H, Tajiri M, Ogawa N, Masuda M, Takahashi T, Sugimura H, Kitamura H: Down-regulation of DUSP6 expression in lung cancers: its mechanism and potential role in carcinogenesis. Am J Pathol 175:867?881, 2009.
7 Otsuka S, Hanibuchi M, Ikuta K, Yano S, Goto H, Ogino H, Yamada T, Kakiuchi S, Nishioka Y, Takahashi T, Sone S: A bone metastasis model with osteolytic and osteoblastic properties of human lung cancer ACC-LC-319/bone 2 in natural killer cell-depleted severe combined immunodeficient mice. Oncol Res 17:581-591, 2009.
8 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: p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation. Biochem Biophys Res Commun 383: 411-416, 2009.
9 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: 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. Leukemia 23: 1270-1277, 2009.
10 Gao S, Murakami M, Ito H, Yoshida K, Tagawa Y, Hagiwara K, Takagi A, Kojima T, Suzuki M, Banno Y, Nozawa Y, Murate T: Mechanism of Increased PLD1 Gene Expression During Early Adipocyte Differentiation Process of Mouse Cell Line, 3T3-L1. J Cell Biochem 9:375-382, 2009.
11 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: Mutated Ras induced PLD1 gene expression in human colon cancer cell lines and a mouse cell line of NIH3T3. Nagoya J Med Sci 71: 127-136, 2009.
12 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: Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta 1789: 681-690, 2009.

 

2008

1 Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H, Takahashi T: Identification of HIF-1? as a novel target for miR-17-92 microRNA cluster. Cancer Res 68: 5540-5545, 2008.
2 Osada H, Tomida S, Yatabe Y, Tatematsu Y, Takeuchi T, Murakami H, Kondo Y, Sekido Y, Takahashi T: Roles of ASH1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. Cancer Res 68:1647-1655, 2008.
3 Tokumaru S, Suzuki M, Yamada H, Nagino N, Takahashi T: let-7 regulates Dicer expression and constitutes a negative feedback loop. Carcinogenesis 29: 2073-2077, 2008.
4 Yamada H, Yanagisawa K, Tokumaru S, Taguchi A, Nimura Y, Osada H, Nagino M, Takahashi T: Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer 47: 810-818, 2008.
5 Yatabe Y, Takahashi T, Mitsudomi T: Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res 68: 2106-2111, 2008.
6 Shimizu J, Horio Y, Osada H, Hida T, Hasegawa Y, Shimokata K, Takahashi T, Sekido Y, Yatabe Y: mRNA expression of RRM1, ERCC1 and ERCC2 is not associated with chemosensitivity to cisplatin, carboplatin and gemcitabine in human lung cancer cell lines. Respirology 13: 510-517, 2008.
7 Arima C, Hakamada K, Okamoto M, Hanai T: Modified Fuzzy Gap Statistic for Estimating Preferable Number of Clusters in Fuzzy k-Means Clustering. J Biosci Bioeng 105:273-281, 2008.
8 Iwasaki T, Murakami M, Sugisaki C, Sobue S, Ohashi H, Asano H, Suzuki M, Nakamura S, Ito M, Murate T: 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. Pathol Int 58: 353-360, 2008.
9 Sobue S, Murakami M, Banno Y, Ito H, Kimura A, Gao S, Furuhata A, Takagi A, Kojima T, Suzuki M, Nozawa Y, Murate T: v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization: alteration of AU-rich element-binding proteins. Oncogene 27: 6023-6033, 2008.
10 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: Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells. Int J Hematol 87: 266-275, 2008.
11 Takemura M, Sugimura K, Okumura K, Limsirichaikul S, Suzuki M, Yamada Y, Yoshida S: Hyper-phosphorylated retinoblastoma protein suppresses telomere elongation. Biosci Biotechnol Biochem 72: 630-635, 2008.

 

2007

1 Tomida S*, Yanagisawa K*, Koshikawa K, Yatabe Y, Mitsudomi T, Osada H, Takahashi T: Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach. Oncogene 26: 4600-4608, 2007. (*equal contributors)
2 Yanagisawa K*, Tomida S*, Shimada Y, Yatabe Y, Mitsudomi T, Takahashi T: A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer. J Natl Cancer Inst 99: 858-867, 2007. (*equal contributors)
3 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. Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res. 67: 6007-6011, 2007. (*equal contributors)
4 Ebi H, Matsuo K, Sugito N, Suzuki M, Osada H, Tajima K, Ueda R, Takahashi T: Novel NBS1 heterozygous germline mutation causing MRE11-binding domain loss predisposes to common types of cancer. Cancer Res 67: 11158-11165, 2007.
5 Nagai H, Sugito N, Matsubara H, Tatematsu Y, Hida T, Sekido Y, Nagino M, Nimura Y, Takahashi T, Osada H: CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. Oncogene 26: 4025-4031, 2007.
6 Matsubara H*, Takeuchi T*, Nishikawa E*, Yanagisawa K, Hayashita Y, Ebi H, Yamada H, Suzuki M, Nagino M, Nimura Y, Osada H, Takahashi T: Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene 26:6099-6105, 2007.
7 Nicolescu A C, Comeau J L, Hill B C, Bedara L L, Takahashi T, Brien J F, Racz W J, Massey T E: Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of cytoprotection by spin trapping nitorones. Toxicol Appl Pharmacol 220: 60-71, 2007.
8 Yamashita D, Sano Y, Adachi Y, Okamoto Y, Osada H, Takahashi T, Yamaguchi T, Osumi T, Hirose F: hDREF regulates cell proliferation and expression of ribosomal protein genes. Mol Cell Biol 27: 2003-2013, 2007.
9 Ranganathan P, Agrawal A, Bhushan R, Chavalmane A K, Kalathur R K R, Takahashi T, Kondaiah P: Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells. BMC Genomics 8: 98, 2007.
10 Sadeghi M M, Esmailzadeh L, Zhang J, Guo X, Asadi A, Krassilnikova S, RastegarFassaei H, Luo G, Al-Lamki R S M, Takahashi T, Tellides G, Bender J R, Rodriguez E R: ESDN is a marker of vascular remodeling and regulator of cell proliferation in graft arteriosclerosis. Am J Transplant 7: 2098-2105, 2007.
11 Majidi M, Al-Wadei H A, Takahashi T, Schuller H M: Non-genomic ? estrogen receptors enhance ?1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells. Cancer Res 67: 6863-6871, 2007.
12 Sakamoto H, Shimizu J, Horio Y, Ueda R, Takahashi T, Mitsudomi T, Yatabe Y: Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol 212: 287-294, 2007.
13 Onozato R, Kosaka T, Achiwa H, Kuwano H, Takahashi T, Yatabe Y Mitsudomi T. LKB1 gene mutations in Japanese lung cancer patients. Cancer Sci 98: 1747-1751, 2007.
14 Kikuchi R, Murakami M, Sobue S, Iwasaki T, Hagiwara K, Takagi A, Kojima T, Asano H, Suzuki M, Banno Y, Nozawa Y, Murate T: Ewing's sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5' promoter. Oncogene 26: 1802-1810, 2007.
15 Kikuchi R, Sobue S, Murakami M, Ito H, Kimura A, Iwasaki T, Shibayama S, Takagi A, Kojima T, Suzuki M, Banno Y, Nozawa Y, Murate T: Mechanism of vitamin D3-induced transcription of phospholipase D1 in HaCat human keratinocytes. FEBS Lett 581: 1800-1804, 2007.
16 Murakami M, Ichihara M, Sobue S, Kikuchi R, Ito H, Kimura A, Iwasaki T, Takagi A, Kojima T, Takahashi M, Suzuki M, Banno Y, Nozawa Y, Murate T: RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis. J Neurochem 102: 1585-1594 2007
17 Ram K S, Inagaki M, Yamaguchi T, Thomas B S, Harish C P: Role of Phosphorylation on the Structural Dynamics and Function of Types III and IV Intermediate Filaments. Exp Cell Res 313: 2098-2109, 2007

 

2006

1 Takeuchi T*, Tomida S*, Yatabe Y, Kosaka T, Osada H, Yanagisawa K, Mitsudomi T, Takahashi T: Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. J Clin Oncol 24: 1679-1688, 2006. (*equal contributors)
2 Maeno K, Masuda A, Yanagisawa K, Konishi H, Osada H, Saito T, Ueda R, Takahashi T: Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers. Oncogene 25: 271-277, 2006.
3 Yatabe Y, Hida T, Horio Y, Kosaka T, Takahashi T, Mitsudomi T: A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer. J Mol Diagn 8: 335-341, 2006.
4 Al-Wadei H A, Takahashi T, Schuller H M: Caffeine stimulates the proliferation of human lung adenocarcinoma cells and small airway epithelial cells via activation of PKA, CREB and ERK1/2. Oncol Rep15: 431-435, 2006.
5 Ko K, Furukawa K, Takahashi T, Urano T, Sanai Y, Nagino M, Nimura Y, Furukawa K: Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers. Oncogene 25: 6924-6935, 2006.
6 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. Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia. Am J Pathol 169: 1550-1566, 2006.
7 Pavlov YI, Frahm C, Nick McElhinny S A, Niimi A, Suzuki M, Kunkel T A: Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta. Curr Biol 16: 202-207, 2006.
8 Sobue S, Iwasaki T, Sugisaki C, Nagata K, Kikuchi R, Murakami M, Takagi A, Kojima T, Banno Y, Akao Y, Nozawa Y, Kannagi R, Suzuki M, Abe A, Naoe T, Murate T: Quantitative RT-PCR analysis of sphingolipid metabolic enzymes in acute leukemia and myelodysplastic syndromes. Leukemia 20: 2042-2046, 2006.
9 Nishimura T, Yamaguchi T, Tokunaga A, Hara A, Hamaguchi T, Kato K, Iwamatsu A, Okano H, Kaibuchi K: Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2. Mol Biol Cell 17: 1273-1285, 2006
10 Oguri T, Inoko A, Shima H, Izawa I, Arimura N, Yamaguchi T, Inagaki N, Kaibuchi K, Kikuchi K, Inagaki M: Vimentin-Ser82 as a memory phosphorylation site in astrocytes. Genes to Cells 11: 531-540 2006

 

2005

1 Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Kawahara K, Sekido Y, Takahashi T: A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 65: 9628-9632, 2005. (*equal contributors)
2 Osada H, Tatematsu Y, Yatabe Y, Horio Y, Takahashi T: The ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Cancer Res. 65: 10680-10685, 2005. 
3 Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, Yatabe Y, Takamizawa J, Miyoshi S, Mitsudomi T, Takahashi T: Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci 96: 111-115, 2005.
4 Osada H, Tatematsu Y, Sugito N, Horio Y, Takahashi T: Histone modification in the TGFβRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines. Mol Carcinog 44: 233-241, 2005.
5 Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, Hatooka S, Shinoda M, Takahashi T, Yatabe Y: 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. J Clin Oncol 23: 2513-2520, 2005.
6 Yatabe Y, Kosaka T, Takahashi T, Mitsudomi T: EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 29: 633-639, 2005.
7 He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K: Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 65: 4739-4746, 2005.
8 Anumanthan G, Halder S K, Osada H, Takahashi T, Massion P P, Carbone D P, Datta P K: Restoration of TGF-? signaling reduces tumorigenecity in human lung cancer cells. Br J Cancer 93: 1157-1167, 2005. 
9 Hussein A, Al-Wadei N, Takahashi T, Shuller H: Theophylline stimulates cAMP-mediated signaling associated with growth regulation in human cells from pulmonary adenocarcinoma and small airway epithelia. Int J Oncol 27: 155-160, 2005.
10 Al-Wadei H A, Takahashi T, Schuller H M: Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by ??carotene via activation of cAMP, PKA, CREB and ERK1/2. Int J Cancer 118:1370-1380, 2005.
11 Sobue S, Hagiwara K, Banno Y, Tamiya-Koizumi K, Suzuki M, Takagi A, Kojima T, Asano H, Nozawa Y, Murate T: Transcription factor specificity protein 1 (Sp1) is the main regulator of nerve growth factor-induced sphingosine kinase 1 gene expression of the rat pheochromocytoma cell line, PC12. J Neurochem, 95: 940-949, 2005.
12 Yamaguchi T, Goto H, Yokoyama T, Sillj? H, Hanisch A, Uldschmid A, Takai Y, Oguri T, Nigg E A, Inagaki M: Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis. J Cell Biol 171: 431-436, 2005
13 Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, Hoshino M, Kaibuchi K: PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7: 270-277, 2005

 

2004

1 Nakagawa T, Hayashita Y, Maeno K, Masuda A, Sugito N, Osada H, Yanagisawa K, Ebi H, Shimokata K, Takahashi T: Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines. Cancer Res 2004; 64: 4826-4832.
2 Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada T, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T: Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64: 3753-3760
3 Tomida S, Koshikawa K, Yatabe Y, Harano T, Ogura N, Mitsudomi T, Some M, Takahashi T, Osada H, Takahashi T: Gene expression-based, individualized outcome prediction of surgically treated lung cancer patients. Oncogene 2004, 23: 5360-5370.
4 Yatabe Y, Mitsudomi T, Takahashi T: Cellular property-associated expression of maspin controlled by promoter DNA methylation in normal lung and non-small cell lung cancers. Oncogene 2004; 23: 4041-4049.
5 Niimi A, Limsirichaikul S, Yoshida S, Iwai S, Masutani C, Hanaoka F, Kool E T, Nishiyama Y, Suzuki M: Palm mutants in DNA polymerases alpha and eta alter DNAreplication fidelity and translesion activity. Mol Cell Biol 2004; 24: 2734-2746.
6 Osada H, Tatematsu Y, Saito H, Yatabe Y, Mitsudomi T, Takahashi T: Reduced expression of class II HDAC genes are associated with poor prognosis in lung cancer patients. Int J Cancer 2004; 112:26-32.
7 Suda N, Ito Y, Imai T, Kikumori T, Kikuchi A, Nishiyama Y, Yoshida S, Suzuki M: The alpha4 residues of human DNA topoisomerase IIalpha function in enzymatic activity and anticancer drug sensitivity: Nucleic Acids Res 2004; 32(5): 1767-1773.
8 Yatabe Y, Koga T, Mitsudomi T, Takahashi T: A subset of lung adenocarcinoma with CK20 and CDX20 expression, K-ras mutation and goblet cell morphology. J Pathol 2004; 203: 645-652.
9 Kosaka T, Yatabe Y, Endoh H, Takahashi T, Mitsudomi T: Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res (in press).
10 Endoh H, Tomida S, Yatabe Y, Konishi H, Osada H, Tajima K, Kuwano H, Takahashi T, Mitsudomi T: Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time RT-PCR. J Clin Oncol 2004; 22:  811-819.
11 Okudera K, Hayashi H, Ito T, Yazawa T, Suzuki T, Nakane Y, Sato H, Ishi H, Keqin X Masuda A, Takahashi T, Kitamura H: 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). Am J Pathol 2004; 164: 91-100.
12 Hashimoto M, Ichihara M, Watanabe T, Kawai K, Koshikawa K, Yuasa N, Takahashi T, Yatabe Y, Murakumo Y, Zhang J M, Nimura Y, Takahashi M: Expression of CD109 in human cancer. Oncogene 2004; 23: 3716-3720.
13 Iwafuchi H, Mori N, Takahashi T, Yatabe Y: Phenotypic composition of salivary gland tumors; an application of principle component analysis to tissue microarray data. Modern Pathol 2004; 17: 203-210. 
14 Koga T, Horio Y, Mitsudomi T, Takahashi T, Yatabe Y: A novel approach to identifying markers of tissue-specific expression: Use of MGB in the differential diagnosis of lung tumors in patients with a history of breast cancer. J Mol Diag 2004; 6: 90-95.

2003

1 Konishi H, Sugiyama M, Mizuno K, Saito H, Yatabe Y, Takahashi T, Osada H. Takahashi T. Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer. Oncogene 2003; 22: 1892-1905.
2 Masuda A, Maeno K, Nakagawa T, Saito T, Takahashi T: Association between mitotic spindle checkpoint impairment and susceptibility to the induction of apoptosis by antimicrotubule agents in human lung cancers. Am J Pathol 2003; 163: 1106-1119.
3 Ogawa M, Limsirichaikul S, Niimi A, Iwai S, Yoshida S, Suzuki M: Distinct function of conserved amino acids in the fingers of Saccharomyces cerevisiae DNA polymerase alpha. J Biol Chem 2003; 278: 19071-19078.
4 Furuta M, Nozawa K, Takemura M, Izuta S, Murate T, Tsuchiya M, Yoshida K, Taka N, Nimura Y, Yoshida S: A novel platinum compound inhibits telomerase activity in vitro and reduces telomere length in a human hepatoma cell line. Int J Cancer 2003; 104:709-715.
5 Suda N, Nakagawa Y, Kikuchi A, Sawada M, Takami Y, Fuhanashi H, Nakao A, Yoshida S, Suzuki M: Function of the loop residue Thr792 in human DNA topoisomerase IIalpha. Biochem Biophys Res Commun 2003; 303: 46-51.
6 Limsirichaikul S, Ogawa M, Niimi A, Iwai S, Murate T, Yoshida S, Suzuki M: The Gly952 residue of Saccharomyces cerevisiae DNA polymerase alpha is important in discriminating correct deoxyribonucleotides from incorrect ones. J Biol Chem 2003; 278: 19079-19086.
7 Yokoi S, Yasui K, lizasa T, Takahashi T, Fujisawa T, Inazawa J. Downregulation of SKP2 induces apoptosis in lung cancer cells. Cancer Sci 2003; 94: 344-349.
8 Endoh H, Yatabe Y, Shimizu S, Tajima K, Kuwano H, Takahashi T, Mitsudomi T: RASSF1 gene inactivation in non-small cell lung cancer and its clinical implication. Int J Cancer 2003; 106: 45-51.
9 Tajima K, Obata Y, Tamaki H, Yshida M, Chen Y -T, Scanloan M J, Old L J, Kuwano H, Takahashi T, Takahashi T, Mitsudomi T: Expression of cancer/testis (CT) antigens in lung cancer. Lung Cancer 2003; 42: 23-33.
10 Suzuki T, Nakagawa T, Endo H, Mitsudomi T, Masuda A, Yatabe Y, Sugiura T, Takahashi, T, Hida T: The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 (‘Iressa’) is not related to the expression of EGFR or HER-2 or to K-ras gene status. Lung Cancer 2003; 42: 35-41.
11 Hanai T, Yatabe Y, Nakayama Y, Takahashi T, Honda H, Mitsudomi T, Kobayashi T: Prognostic models in patients with non-small-cell lung cancer using artificial neural networks in comparison with logistic regression. Cancer Sci 2003; 94: 473-477.
12 Cheng R Y S, Zhao A, Alvord W G, Powell D A, Bare R M, Masuda A, Takahashi T, Anderson L M, Kasprzak K S: Gene expression dose-response changes in microarrays after exposure of human peripheral lung epithelial cells to nickel(II). Toxicol Appl Pharm 2003; 191:22-39.
13 Kurumiya Y, Nagino M, Nozawa K, Kamiya J, Uesaka K, Sano T, Yoshida S, Nimura Y: Biliary bile acid concentration is a simple and reliable indicator for liver function after hepatobiliary resection for biliary cancer. Surgery 2003: 133; 512-520.
14 Virmani A, Rathi A, Sugio K, Sathyanarayana U G, Toyooka S, Kischel F C, Tonk V, Padar A, Takahashi T, Roth J A, Euhus D M, Minna J D, Gazdar A: Aberrant methylation of TMS1 in small cell, non-small cell lung cancer and breast cancer. Int  J Cancer 2003; 106: 198-204.
15 Sithananda G, Smith G T, Masuda A, Takahashi T, Anderson L M, Fornwald L W: Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phospatidylinositol3 kinase/Akt pathway. Carcinogenesis 2003; 24: 1581-1592
16 Virmani A, Rathi A, Sugio K, Heda S, Lewis C, Tonk V, Takahashi T, Roth J A, Minna J D, Euhus D M, Gazdar A F: Aberrant methylation of the cyclin D2 promoter in primary small cell, non-small cell and breast cancers. Int J Cancer 2003; 107: 341-345.
17 Murakami C, Yamazaki T, Hanashima S, Takahashi S, Takemura M, Yoshida S, Ohta K, Yoshida H, Sugawara F, Sakaguchi K, Mizushina Y: A novel DNA polymerase inhibitor and a potent apoptosis inducer: 2-mono-O-acyl-3-O-(alpha-D-sulfoquinovosyl)-glyceride with one stearic acid (alpha-SQMG-C18). Biochim Biophys Acta 2003; 1645:72-80.
18 Mizushina Y, Xu X, Asahara H, Takeuchi R, Oshige M, Shimazaki N, Takemura M, Yamaguchi T, Kuroda K, Linn S, Yoshida H, Koiwai O, Saneyoshi M, Sugawara F, Sakaguchi K: A sulfoquinovosyl diacylglycerol is a DNA polymerase epsilon inhibitor. Biochem J 2003; 370:299-305.
19 Mizushina Y, Ishidoh T, Kamisuki S, Nakazawa S, Takemura M, Sugawara F, Yoshida H, Sakaguchi K: Flavonoid glycoside: a new inhibitor of eukaryotic DNA polymerase alpha and a new carrier for inhibitor-affinity chromatography. Biochem Biophys Res Commun 2003; 301:480-487.
20 Mizushina Y, Murakami C, Yogi K, Ueda K, Ishidoh T, Takemura M, Perpelescu M, Suzuki M, Oshige M, Yamaguchi T, Saneyoshi M, Yoshida H, Sakaguchi K: Kohamaic acid A, a novel sesterterpenic acid, inhibits activities of DNA polymerases from deuterostomes. Biochim Biophys Acta 2003; 1468 55-61, 2003
21 Mizushina Y, Xu X, Asano N, Kasai N, Kato A, Takemura M, Asahara H, Linn S, Sugawara F, Yoshida H, Sakaguchi K: The inhibitory action of pyrrolidine alkaloid, 1,4-dideoxy-1,4-imino-D-ribitol, on eukaryotic DNA polymerases. Biochem Biophys Res Commun 2003; 304: 78-85.
22 Mizushina Y, Maeda N, Kawasaki M, Ichikawa H, Murakami C, Takemura M, Xu XN, Sugawara F, Fukumori Y, Yoshida H, Sakaguchi K: Inhibitory action of emulsified sulfoquinovosyl acylglycerol on mammalian DNA polymerases.Lipids. 2003; 38 (10): 1065-1074
23 Mizushina Y, Hirota M, Murakami C, Ishidoh T, Kamisuki S, Shimazaki N, Takemura M, Perpelescu M, Suzuki M, Yoshida H, Sugawara F, Koiwai O, Sakaguchi K: Some anti-chronic inflammatory compounds are DNA polymerase lambda-specific inhibitors Biochem Pharmacol 2003; 66 (10): 1935-1944.
24 Murakami C, Takemura M, Yoshida H, Sugawara F, Sakaguchi K, Mizushina Y: Analysis of cell cycle regulation by 1-mono-O-acyl-3-O-(alpha-D-sulfoquinovosyl)- glyceride (SQMG), an inhibitor of eukaryotic DNA polymerases. Biochem Pharmacol 2003; 66 (4): 541-550.
25 Mizushina Y X X, Murakami C, Okano T, Takemura M, Yoshida H, Sakaguchi K. Selective inhibition of mammalian DNA polymerase alpha by vitamin D-2 and D-3.   J Pharmacol Sci 2003; 92: 283-290.
26 Nakade Y, Banno Y, Tamiya-Koizumi K, Hagiwara K, Sobue S, Koda M, Suzuki M, Kojima T, Takagi A, Asano H, Nozawa Y, Murate T. Regulation of sphingosine kinase 1 gene expression by protein kinase C in a human leukemia cell line, MEG-O1. Biochim Biophys Acta 2003; 1635:104-116.

 

2002

1 Konishi H, Nakagawa T, Harano T, Mizuno K, Saito H, Masuda A, Matsuda H, Osada H, Takahashi T: Identification of frequent G2 checkpoint impairment and a homozygous deletion of 14-3-3? at 17p13.3 in small cell lung cancers. Cancer Res 2002; 62: 271-276.
2 Osada H, Tatematsu Y, Yatabe Y, Nakagawa T, Konishi H, Tezel E, Takahashi T: Frequent and histological type-specific inactivation of 14-3-3?? in human lung cancers. Oncogene 2002; 21: 2418-2424.
3 Koshikawa K, Osada H, Kozaki K, Konishi H, Masuda A, Tatematsu Y, Nakao A, Takahashi T: Significant up-regulation of a novel gene, CLCP1, in a highly metastatic lung cancer subline as well as in lung cancers in vivo. Oncogene 2002; 21: 2822-2828.
4 Mizuno K, Osada H, Konishi H, Tatematsu Y, Fujii Y, Takahashi T: Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers. Oncogene 2002; 21: 2328-2333. 
5 Yatabe Y, Osada H, Tatematsu Y, Mitsudomi T, Takahashi T: Decreased expression of 14-3-3? in neuroendocrine tumors is independent of origin and malignant potential. Oncogene 2002; 21: 8310-8319.
6 Yatabe Y, Mitsudomi T, Takahashi T: TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol 2002; 26: 767-773.
7 Hamajima N, Ito H, Matsuo K, Saito T, Tajima K, Ando M, Yoshida K, Takahashi T: Positive association between smoking habits and dopamine receptor D2 TaqI A polymorphism in Japanese males. J Epidemiol. 2002; 12: 297-304. 
8 Hida T, Kozaki K, Ito H, Miyaishi O, Tatematsu Y, Suzuki M, Seito T, Matsuo K, Sugiura T, Ogawa M, Takahashi T, Takahashi T: Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a cyclooxygenase 2-specific inhibitor, JTE-522, and conventional anticancer agents. Clin Cancer Res 2002; 8: 2443-2447. 
9 He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K: Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 2002; 94: 785-787.
10 Murate T, Suzuki M, Hattori M, Takagi A, Kojima T, Tanizawa T, Asano H, Hotta T, Saito H, Yoshida S, Tamiya-Koizumi K: Up-regulation of acid sphingomyelinase during retinoic acid-induced myeloid differentiation of NB4, a human acute promyelocytic leukemia cell line. J Biol Chem 2002; 277:9936-9943.
11 Suzuki S, Tamai K, Yoshida S: Enzyme-linked immunosorbent assay for distinct cyclin-dependent kinase activities using phosphorylation-site-specific anti-pRb monoclonal antibodies. Anal Biochem 2002; 301:65-74.
12 Akao Y, Kusakabe S, Banno Y, Kito M, Nakagawa Y, Tamiya-Koizumi K, Hattori M, Sawada M, Hirabayashi Y, Ohishi N, Nozawa Y: Ceramide accumulation is independent of camptothecin-induced apoptosis in prostate cancer LNCaP cells. Biochem Biophys Res Commun 2002; 294:363-370.
13 Kai T, Matsunaga R, Eguchi M, Kamiya H, Kasai H, Suzuki M, Izuta S: An oxidized nucleotide affects DNA replication through activation of protein kinases in Xenopus egg lysate. Nucleic Acids Res 2002; 30:569-573.
14 Mizushina Y, Kamisuki S, Shimazaki N, Takemura M, Asahara H, Linn S, Yoshida S, Matsukage A, Koiwai O, Sugawara F, Yoshida H, Sakaguchi K: A plant phytotoxin, solanapyrone A, is an inhibitor of DNA polymerase beta and lambda. J Biol Chem 2002; 277:630-638.
15 Murakami C, Takemura M, Sugiyama Y, Kamisuki S, Asahara H, Kawasaki M, Ishidoh T, Linn S, Yoshida S, Sugawara F, Yoshida H, Sakaguchi K, Mizushina Y: Vitamin A- related compounds, all-trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases. Biochim Biophys Acta 2002; 1574:85-92.
16 Takemura M: Evolution and degeneration of eukaryotic DNA replication system. BioSystems 2002; 65:139-145.
17 Takemura M, Ohoka F, Perpelescu M, Ogawa M, Matsushita H, Takaba T, Akiyama T, Umekawa H, Furuichi Y, Cook PR, Yoshida S: Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23. Exp Cell Res 2002; 276:233-241.
18 Takemura M: Biochemical properties of the stimulatory activity of DNA polymerase alpha by the hyper-phosphorylated retinoblastoma protein. Biochim Biophys Acta 2002; 1571:151-156.
19 Perpelescu M, Kobayashi J, Furuta M, Ito Y, Izuta S, Takemura M, Suzuki M, Yoshida S: Novel phenalenone derivatives from a marine-derived fungus exhibit distinct inhibition spectra against eukaryotic DNA polymerases. Biochemistry 2002; 41:7610-7616.
20 Mizushina Y, Kamisuki S, Kasai N, Ishidoh T, Shimazaki N, Takemura M, Asahara H, Linn S, Yoshida S, Koiwai O, Sugawara F, Yoshida H, Sakaguchi K: Petasiphenol: a DNA polymerase lambda inhibitor. Biochemistry 2002; 41:14463-14471.
21 Tamiya-Koizumi K, Usukura J, Mihara K, Ishihra H, Hirabayashi Y: Sphingomyelin-metabolic enzymes in Triton X-100-insoluble plasma membrane domains of rat liver and hepatoma cells. Chem Phys lipids 2002; 118: 67- 
22 Yokoi-Ishihara S, Yasui K, Saito-Ohara F, Iizasa T, Fujisawa T, Terasaki T, Horii A, Takahashi T, Hirohashi S, Inazawa J: A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol 2002; 161: 207-216. 
23 Martinez J M, Afshari C A, Bushel P R, Masuda A, Takahashi T, Walker N: Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells. Toxicol. Sci. 2002; 69: 409-423. 
24 Kammouni W, Ramkrishna G, Sithanandam G, Smith G T, Fornwald L W, Masuda A, Takahashi T: Anderson L M. Increased K-ras protein and activity in mouse and human lung epithelial cells at confluence. Cell Growth Differ 2002; 13: 441-448.

 

2001

1 Osada H, Tatematsu Y, Masuda A, Saito T, Sugiyama M, Yanagisawa K, Takahashi T: Heterogeneous TGF-beta unresponsiveness and loss of TGFbetaRII expression caused by histone deacetylation in lung cancer cell lines. Cancer Res. 2001; 61: 8331-8339.
2 Kozaki K, Koshikawa K, Tatematsu Y, Miyaishi O, Saito H, Hida T, Osada H, Takahashi T: Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis.  Oncogene 2001; 20: 4228-4234.
3 Haruki N, Harano T, Masuda A, Kiyono T, Tatematsu Y, Shimizu S, Mitsudomi T, Konishi H, Osada H, Fujii Y, Takahashi T: Persistent increase in chromosome instability in lung cancer: possible indirect involvement of p53 inactivation. Am J Pathol 2001; 159: 1345-1352.
4 Masuda A, Osada H, Yatabe Y, Kozaki K, Tatematsu Y, Takahashi T, Hida T, Takahashi T, Takahashi T: Protective function of p27KIP1 against apoptosis in small cell lung cancer cells in unfavorable microenvironments. Am J Pathol 2001; 158: 87-96.
5 Yoshida K, Hamajima N, Kozaki K, Saito H, Maeno K, Sugiura T, Ookuma K, Takahashi T: Association between the dopamine D2 receptor A2/A2 genotype and smoking behavior in the Japanese. Cancer Epidemiol Biomark & Prev 2001; 10: 403-405.
6 Matsuoka S, Nakagawa T, Masuda A, Haruki N, Elledge S J, Takahashi T: Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res 2001; 61: 5362-5365.
7 Dammann R, Takahashi T: Pfeifer G P The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas.  Oncogene 2001; 20: 3563-3567.
8 Tosaka A, Ogawa M, Yoshida S, Suzuki M: O-helix mutant T664P of Thermus aquaticus DNA polymerase I: altered catalytic properties for incorporation of incorrect but not correct nucleotides. J Biol Chem 2001; 276:27562-27567.
9 Yoshida K, Tosaka A, Kamiya H, Murate T, Kasai H, Nimura Y, Ogawa M, Yoshida S, Suzuki M: Arg660Ser mutation in Thermus aquaticus DNA polymerase I suppresses T - C transitions; implication of wobble base pair formation at the nucleotide incorporation step. Nucleic Acids Res 2001; 29:4206-4214.
10 Takemura M, Yamamoto T, Kitagawa M, Taya Y, Akiyama T, Asahara H, Linn S, Suzuki S, Tamai K, Yoshida S: Stimulation of DNA polymerase alpha activity by cdk2-phosphorylated Rb protein. Biochem Biophys Res Commun 2001; 282:984-990.
11 Mizutani Y, Tamiya-Koizumi K, Nakamura N, Kobayashi M, Hirabayashi Y, Yoshida S: Nuclear localization of neutral sphingomyelinase 1: biochemical and immunocytochemical analyses. J Cell Sci 2001; 114:3727-3736.
12 Murate T, Banno Y, Tamiya-Koizumi K, Watanabe K, Mori N, Wada A, Igarashi Y, Takagi A, Kojima T, Asano H, Akao Y, Yoshida S, Saito H, Nozawa Y: Cell type-specific localization of sphingosine kinase 1a in human tissues. J Histochem Cytochem 2001; 49:845-855.
13 Ogawa M, Tosaka A, Itoh Y, Yoshida S, Suzuki M: Enhanced ribonucleotide incorporation by an O-helix mutant of Thermus aquatiqus DNA polymerase I. Mut Res: DNA Repair 2001; 485:197-207.
14 Okada Y, Tosaka A, Nimura Y, Kikuchi A, Yoshida S, Suzuki M: Atypical multidrug resistance may be associated with catalytically active mutants of human DNA topoisomerase II alpha. Gene 2001; 272:141-148.
15 Takemura M: Poxviruses and the origin of the eukaryotic nucleus. J Mol Evol 2001; 52:419-425.
16 Umekawa H, Sato K, Takemura M, Watanabe Y, Usui S, Takahashi T, Yoshida S, Olson MOJ, Furuichi Y: The carboxyl terminal sequence of nucleolar protein B23.1 is important in its DNA polymerase alpha-stimulatory activity. J Biochem 2001; 130:199-205.
17 Mizushina Y, Sugiyama Y, Yoshida H, Hanashima S, Yamazaki T, Kamisuki S, Ohta K, Takemura M, Yamaguchi T, Matsukage A, Yoshida S, Saneyoshi M, Sugawara F, Sakaguchi K: Galactosyldiacylglycerol, a mammalian DNA polymerase alpha-specific inhibitor from a sea alga, Petalonia bingbamiae. Biol Pharm Bull 2001; 24:982-987.
18 Ito Y, Tamiya-Koizumi K, Koide Y, Nakagawa M, Kawade T, Nishida A, Murate T, Takemura M, Suzuki M, Yoshida S: Structural requirements of sphingosine molecules for inhibition of DNA primase: Biochemical and computational analyses. Biochemistry 2001; 40:11571-11577.
19 Takemura M, Yoshida S: Stimulation of DNA polymerase alpha by hyper-gravity generated by centrifugal acceleration. Biochem Biophys Res Commun 2001; 289:345-349.
20 Haruki N, Saito H, Harano T, Nomoto S, Takahashi T, Osada H, Fujii Y, Takahashi T: Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. Cancer Lett 2001; 162: 201-205.
21 Toyooka S, Toyooka K, Maruyama R, Virmani A, Girard L, Miyajima K, Harada K, Ariyoshi Y, Takahashi T, Sugio K, Brambilla E, Gilcrease M, Minna J D, Gazdar A F: DNA methylation profiles of lung tumors. Mol Cancer Ther 2001; 1: 61-67

 

2000

1 Kozaki K, Miyaishi O, Tsukamoto T, Tatematsu Y, Hida T, Takahashi T, Takahashi T: In vivo selected human lung cancer cell line NCI-H460-LNM35 consistently exhibits lymphogenous metastasis via both subcutaneous and orthotopic propagation. Cancer Res 2000; 60: 2535-2540.
2. Haruki N, Saito H, Tatematsu Y, Konishi H, HaranoT, Masuda A, Fujii Y. Takahashi T: Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. Cancer Res 2000; 60: 4689-4692.
3. Yanagisawa K, Uchida K, Nagatake M, Masuda A, Sugiyama M, Saito T, Yamaki K, Takahashi T, Osada H: Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers. Oncogene 2000; 19: 2305-2311.
4. Yatabe Y, Konishi H, Mitsudomi T, Nakamura S, Takahashi T: Topographical distributions of allelic loss in individual non-small cell lung cancers. Am J Pathol 2000; 157: 985-93.
5. Okada Y, Ito Y, Kikuchi A, Nimura Y, Yoshida S, Suzuki M: Assignment of functional amino acids around the active site of human DNA topoisomerase II?. J Biol Chem 2000; 275:24630-24638.
6. Suzuki M, Yoshida S, Adman ET, Blank A, Loeb LA: Thermus aquaticus DNA polymerase I mutants with altered fidelity: Interacting mutations in the O helix. J Biol Chem 2000; 275:32728-32735.
7. Shimizu S, Yatabe Y, Koshikawa T, Haruki N, Hatooka S, Shinode M, Suyama M, Ogawa M, Hamajima N, Ueda R, Takahashi T, Mitsudomi T: High frequency of clonally related tumors in cases of multiple synchronous lung cancers as revealed by molecular diagnosis. Clin Cancer Res 2000; 6: 3994-3999.
8. Mitsudomi T, Hamajima N, Ogawa M, Takahashi T: Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res 2000; 6: 4055-4063.
9. Hida T, Kozaki K, Muramatsu H, Masuda A, Shimizu S, Mitsudomi T, Sugiura T, Ogawa M, Takahashi T: Cyclooxygenase (COX)-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 2000; 6: 2006-2011.
10. Dragani T A, Hirohashi S, Juji T, Kawajiri K, Kihara M, Ono-Kihara M, Manenti G, Nomoto T, Sugimura H, Genka K, Yokota J, Takahashi T, Mitsudomi T, Nagao M: Population-based mapping of pulmonary adenoma susceptibility 1 (PAS1) locus. Cancer Res 2000; 60: 5017-5020.
11. Mizutani Y, Tamiya-Koizumi K, Irie F, Hirabayashi Y, Miwa M, Yoshida S: Cloning and expression of rat neutral sphingomyelinase: enzymological characterization and identification of essential histidine residues. Biochim Biophys Acta 2000; 1485:236-246.
12. Mizushina Y, Kamisuki S, Mizuno T, Takemura M, Asahara H, Linn S, Yamaguchi T, Matsukage A, Hanaoka F, Yoshida S, Saneyoshi M, Sugawara F, Sakaguchi K: Dehydroaltenusin, a mammalian DNA polymerase alpha inhibitor. J Biol Chem 2000; 275:33957-33961.
13. Nomoto S, Haruki N, Tatematsu Y, Konishi H, Mitsudomi T, Takahashi T, Takahashi T:  Frequent allelic imbalance suggests the involvement of a tumor suppressor gene at 1p36 in the pathogenesis of human lung cancers. Genes Chrom Cancer 2000; 28:342-346.
14. Nozawa K, Suzuki M, Takemura M, Yoshida S: In vitro expansion of mammalian telomere repeats by DNA polymerase alpha-primase. Nucleic Acids Res 2000; 28:3117-3124.
15. Hamajima N, Saito T, Matsuo K, Kozaki K. -K, Takahashi T, Tajima K: Polymerase chain reaction with confronting two-pair primers for polymorphism genotyping. Jpn J Cancer Res 2000; 91: 865-868.
16. Haruki N, Yatabe Y, Travis W D, Nomoto S, Osada H, Nakamura S, Nakao A, Fujii Y, Takahashi T: Characterization of high-grade neuroendocrine tumors of the lung in relation to menin mutations. Jpn J Cancer Res 2000; 91: 317-323.
17. Kurumiya Y, Nozawa K, Sakaguchi K, Nagino M, Nimura Y, Yoshida S: Differential suppression of liver-specific genes in regenerating rat liver induced by extended hepatectomy. J Hepatol 2000; 32:636-644.
18. Nagasaka A, Nakai A, Oda N, Kotake M, Iwase K, Yoshida S: Reverse transcriptase is elevated in the thyroid tissue from Graves' disease patients. Clin Endocrinol 2000; 53:155-159.
19. Sakaguchi K, Takeuchi E, Suzuki M, Oda K, Nagino M, Nimura Y, Yoshida S: DNA polymerases and Ki-67 nuclear antigen are induced in correlation with the resected mass of rat liver up to 90%. Langenbeck's Arch Surg 2000; 385:135-142.
20. Suzuki S, Suzuki M, Yoshida S: Characterization of the human DNA polymerase delta catalytic subunit expressed by a recombinant baculovirus. Nagoya J Med Sci 2000; 63:99-113.
21. Arinaga M, Shimizu S, Gotoh K, Haruki N, Takahashi T, Takahashi T, Mitsudomi T: Expression of human telomerase subunit genes in primary lung cancer and its clinical significance. Ann Thor Surg 2000; 70: 401-405.