宮城県立がんセンター研究所外観 宮城県立がんセンター

宮城県立がんセンター > 宮城県立がんセンター研究所 > 研究活動紹介:発がん制御研究部

発がん制御研究部

研究員構成

  • 安田 純部長
    東北大学東北メディカル・メガバンク客員教授
  • 山口 壹範上席主任研究員
    東北大学医学系研究科連携講座 がんウイルス学分野 教授
  • 中村 真央研究技師
  • 高梨 友花技術員
  • 初沢 悠人博士課程(東北大学消化器外科)
  • 菅村 和夫特任部長
    東北大学医学系研究科  客員教授・名誉教授

研究紹介

近年、腫瘍は均一でクローナルな細胞集団ではなく、異なる性質をもった亜集団(subpopulation)により構成されていることが知られてきた。中でも「がん幹細胞」は自己複製能、増殖分化能、抗がん剤耐性を併せ持つことから、腫瘍の悪性形質の中心に位置付けられている。がん幹細胞の存在は、急性骨髄性白血病、脳腫瘍、乳がん等のがん種で報告され、今日、他の多くのがん種においても究極の治療標的として注目されている。当研究部では、NOGマウスを用いて種々のヒトがんにおけるがん幹細胞の同定と治療標的分子の探索を目指している。NOGマウスは当研究部の菅村らが樹立したサイトカイン受容体γc鎖欠損マウスとNOD-scid免疫不全マウスを交配して樹立された超免疫不全マウスであり、種々のヒトがん細胞の移植が可能なことから、がん幹細胞の選別に最適な系として知られている。我々は、このNOGマウスへの腫瘍移植系を活用することで、腫瘍悪性形質の発生・維持機構を解明し、最終的に種々のヒトがんに対する新規分子標的治療法や悪性度診断法の開発を目指している。

なお、平成30年度からは東北大学より安田純が着任した。これまでの当研究室の業績を生かしながら今後、がんの個別化医療を目指したゲノム解析研究にも着手する。具体的には早晩保険収載が期待されるがんの遺伝子パネル診断の研究面からの支援や、得られる遺伝子情報を活用したリキッドバイオプシーなど各種の解析技術の開発など、がんのゲノム医療の実現に資する研究開発を推進する

現在の研究課題

  • がんゲノム医療の支援のための研究開発

    分子標的薬剤の開発の進展と、次世代シークエンサーによるがんのゲノム診断技術の進歩によって、がんを惹起するドライバー変異に対して適切な抗がん剤を投与すればこれまで経験されなかったような顕著な治療効果が得られる症例が出現してきた。また、近年注目されている免疫チェックポイント療法も、がんのゲノム異常が高度に蓄積している症例に有効性が高いことも知られてきている。  一方で、ゲノム解析は高額であるにも関わらず、必ずしもすべての患者に福音をもたらすわけではない。例えば上記のような奏効する分子標的薬剤を選択可能な症例は2018年の時点で全体の1割から4割と見積もられており、残りの患者には現在でもゲノム解析の恩恵があるとは言いにくい。保険収載され、日常的にがん遺伝子の変異情報を臨床に有効活用していくために、当研究室では以下の取り組みを実施する。

    1) リキッドバイオプシー(がん組織でなく血液でのがんゲノム診断)の研究開発

    2) 遺伝子パネル検査結果の分析や解釈のための知識や経験を持つ生命情報科学技術の開発

    3) 遺伝子パネル検査結果のさらなる活用のためのデータベース整備と新規分析技術の開発

    1)はオーダーメイドの腫瘍マーカーとして樹立される。結果として組織生検などの患者への負担の軽減や遠隔地から画像診断を受けるために来院する手間などが省けるなど、患者への利益の大きな技術開発である。2)は日進月歩の化学療法の進歩を踏まえ、患者のがんゲノム情報に基づいて遅滞なく新規治験などへの参加勧奨などを実施することが可能になる。3)は今後再発など、患者のフォローアップに際してゲノム情報が活用できる可能性を探索するために必要な取り組みである。これらによって、がんゲノム診断に際し、適切な薬剤の見つからない患者へも何らかの恩恵が得られることが期待される。

  • ATLの造腫瘍性に関わるCA9の役割と免疫治療法の開発

    ATLはHTLV-I (human T-cell leukemia virus type I)感染から数十年を経て発症し、その病態には急性型、慢性型、リンパ腫型、くすぶり型の4型が存在する。これら病型間で悪性度に大きな違いがあるが、その発症機序については未だ不明な点が多い。本センター血液内科診療科長の佐々木治医師(研究所特任研究員を兼務)らと共に、NOGマウスにおける造腫瘍性を悪性度の指標として、造腫瘍性に関わる機能分子の同定を行なっている。

    ATL由来細胞株ST1をNOGマウスに移植継代して得られたST1-N6細胞株はAKTシグナル伝達系の持続的な活性化とNOGマウスにおける強い造腫瘍性を示した(Cancer Sci. 2016)。ST1-N6と親株ST1に発現する遺伝子を比較解析し、ST1-N6で高発現するCA9(carbonic anhydrase IX、炭酸脱水酵素)を同定した。ST1細胞へ野生型CA9を導入すると、造腫瘍性の増強が誘導されるが、CA9酵素活性欠失変異型を導入すると、造腫瘍性の増強は見られなかった。また、CA9shRNA導入によりST1高発現細胞の造腫瘍性は抑制された。これらの結果から、ATL由来ST1細胞の造腫瘍性にCA9酵素活性が深く関わっていることが明らかになった。他方、ATL患者由来リンパ節組織において、CA9+CD25+ATL細胞が検出されたことから、リンパ腫型ATLの悪性形質とCA9発現との関連性が示唆された。従来、CA9は二酸化炭素と水から重炭酸イオンと水素イオンを生成する酵素であり、低酸素下での腫瘍組織のpH調整に関わることが知られており、ATLでの造腫瘍性への関与も想定される。現在、CA9に対するヒト化単クロン抗体を調製し、リンパ腫型ATLに対する免疫療法の可能性を追求している。このほかST1-N6で見られた代謝変動や細胞間接着に関しても検討を行なっている。

  • 遺伝子改変NK細胞を用いたがん免疫療法の開発

    自然免疫を担うNatural killer細胞(NK細胞)は、細菌やウイルスに感染した細胞だけでなく、発生初期のがん細胞排除にも機能していることが知られているが、同様の機能を持つT細胞に比較してがん治療への応用は遅れている。現在注目されているキメラ抗原受容体導入T細胞(CAR-T)は、患者T細胞に腫瘍認識抗体とシグナル分子の融合遺伝子を導入した細胞で、患者に再移入した場合、腫瘍に集積し細胞障害活性を示す。肺がんやメラノーマなど難治性がんに対して、短期の腫瘍退縮、長期の腫瘍抑制効果を示す例も報告されているが、一方で細胞の調製に期間を要する、治療費が高額になる、などの問題も指摘されている。これらの問題を克服するため、T細胞と同様に細胞障害活性をもつNK細胞に我々は着目し、特に臨床試験でヒトへの投与に関する安全性が示されている樹立NK細胞株(NK-92)を対象に、がん免疫療法開発に向けた基礎研究を進めている。NK-92は各種がん細胞株に対する細胞障害活性が極めて高いが、さらにFc受容体やCARを発現させることにより、腫瘍特異的な細胞障害活性を亢進させることに成功した。現在、CA9、IL-2Rβ、CD271(がん幹細胞研究部との共同研究)を標的分子とした治療用NK細胞の作成に取り組み、免疫不全NOGマウスを用いたin vivo移植系での有効性などを検証している。さらに、NK細胞の腫瘍への集積を高めるための遺伝子改変も進めている。

  • 膵がんにおけるがん関連遺伝子の機能解析

    膵がんは消化器がんの中でも特に難治性で、新たな治療法の開発が強く望まれている。これまで研究部で解析を進めてきたCA9に加え、TGFβシグナルの調節因子CD109の膵がんにおける機能解析を進めている(東北大医学部消化器外科との共同研究)。

発表論文リスト

2018年

  • Shibuya, Y, Tokunaga, H, Saito, S, Shimokawa, K, Katsuoka, F, Bin, L, Kojima, K, Nagasaki, M, Yamamoto, M, Yaegashi, N and Yasuda, J, Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing, Genes Chromosomes Cancer, 57, 2, 51-60, 2018
  • Mimori, T, Yasuda, J, Kuroki, Y, Shibata, TF, Katsuoka, F, Saito, S, Nariai, N, Ono, A, Nakai-Inagaki, N, Misawa, K, Tateno, K, Kawai, Y, Fuse, N, Hozawa, A, Kuriyama, S, Sugawara, J, Minegishi, N, Suzuki, K, Kinoshita, K, Nagasaki, M and Yamamoto, M, Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing, Pharmacogenomics J, 2018
  • *Yamaguchi-Kabata, Y, Yasuda, J, Tanabe, O, Suzuki, Y, Kawame, H, Fuse, N, Nagasaki, M, Kawai, Y, Kojima, K, Katsuoka, F, Saito, S, Danjoh, I, Motoike, IN, Yamashita, R, Koshiba, S, Saigusa, D, Tamiya, G, Kure, S, Yaegashi, N, Kawaguchi, Y, Nagami, F, Kuriyama, S, Sugawara, J, Minegishi, N, Hozawa, A, Ogishima, S, Kiyomoto, H, Takai-Igarashi, T, To, MSG, Kinoshita, K and Yamamoto, M, Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals, J Hum Genet, 63, 2, 213-230, 2018
  • *Tanikawa, C, Kamatani,Y, Takahashi, A, Momozawa, Y, Leveque, K, S, Nagayama, S, Mimori, K, Mori, M, Ishii, H, Inazawa, Yasuda, J, Tsuboi, A, Shimizu, A, Sasaki, M, Yamaji, T, Sawada, N, Iwasaki, M, Tsugane, S, Naito, M, Wakai, K, Koyama, T, Takezaki, T, Yuji, K, Murakami, Y, Nakamura, Y, Kubo, M, and Matsuda, K, GWAS identifies two novel colorectal cancer loci at 1 16q24.1 and 20q13.12, Carcinogenesis. 2018 May 3;39(5):652-660.
  • Sakai M, Takeuchi H, Yu Z, Kikuchi Y, Ono C, Takahashi Y, Ito F, Matsuoka H, Tanabe O, Yasuda J, Taki Y, Kawashima R, Tomita H. Polymorphisms in the microglial marker molecule CX3CR1 affect the blood volume of the human brain. Psychiatry Clin Neurosci. 2018 Feb 28. doi: 10.1111/pcn.12649.
  • Miyagi T, Takahashi K, Yamamoto K, Shiozaki K, Yamaguchi K. Biological and Pathological Roles of Ganglioside Sialidases. Prog Mol Biol Transl Sci, 156, 121-150 (2018)

2017年

  • *Pan, X, Nariai, N, Fukuhara, N, Saito, S, Sato, Y, Katsuoka, F, Kojima, K, Kuroki, Y, Danjoh, I, Saito, R, Hasegawa, S, Okitsu, Y, Kondo, A, Onishi, Y, Nagami, F, Kiyomoto, H, Hozawa, A, Fuse, N, Nagasaki, M, Shimizu, R, Yasuda, J, Harigae, H and Yamamoto, M, Monitoring of minimal residual disease in early T-cell precursor acute lymphoblastic leukaemia by next-generation sequencing, Br J Haematol, 176, 2, 318-321, 2017
  • Hachiya, T, Furukawa, R, Shiwa, Y, Ohmomo, H, Ono, K, Katsuoka, F, Nagasaki, M, Yasuda, J, Fuse, N, Kinoshita, K, Yamamoto, M, Tanno, K, Satoh, M, Endo, R, Sasaki, M, Sakata, K, Kobayashi, S, Ogasawara, K, Hitomi, J, Sobue, K and Shimizu, A, Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies, NPJ Genom Med, 2, 11, 2017
  • Hamanaka, T, Kimura, M, Sakurai, T, Ishida, N, Yasuda, J, Nagasaki, M, Nariai, N, Endo, A, Homma, K, Katsuoka, F, Matsubara, Y, Yamamoto, M and Fuse, N, A Histologic Categorization of Aqueous Outflow Routes in Familial Open-Angle Glaucoma and Associations With Mutations in the MYOC Gene in Japanese Patients, Invest Ophthalmol Vis Sci, 58, 5, 2818-2831, 2017
  • Nishioka, M, Bundo, M, Ueda, J, Katsuoka, F, Sato, Y, Kuroki, Y, Ishii, T, Ukai, W, Murayama, S, Hashimoto, E, Nagasaki, M, Yasuda, J, Kasai, K, Kato, T and Iwamoto, K, Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders, Psychiatry Clin Neurosci, 2017
  • Shiga, Y, Nishiguchi, KM, Kawai, Y, Kojima, K, Sato, K, Fujita, K, Takahashi, M, Omodaka, K, Araie, M, Kashiwagi, K, Aihara, M, Iwata, T, Mabuchi, F, Takamoto, M, Ozaki, M, Kawase, K, Fuse, N, Yamamoto, M, Yasuda, J, Nagasaki, M, Nakazawa, T and Japan Glaucoma Society Omics, G, Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7, PLoS One, 12, 12, e0186678, 2017
  • Takahashi K, Proshin S, Yamaguchi K, Yamashita Y, Katakura R, Yamamoto K, Shima H, Hosono M, Miyagi T. Sialidase NEU3 defines invasive potential of human glioblastoma cells by regulating calpain-mediated proteolysis of focal adhesion proteins. Biochim Biophys Acta, 1861, 2778-2788 (2017)
  • Seyrantepe V, Demir SA, Timur ZK, Von Gerichten J, Marsching C, Erdemli E, Oztas E, Takahashi K, Yamaguchi K, Ates N, Donmez Demir B, Dalkara T, Erich K, Hopf C, Sandhoff R, Miyagi T. Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease. Exp Neurol, 299, 26-41 (2017)
  • Pan X, De Aragao CBP, Velasco-Martin JP, Priestman DA, Wu HY, Takahashi K, Yamaguchi K, Sturiale L, Garozzo D, Platt FM, Lamarche-Vane N, Morales CR, Miyagi T, Pshezhetsky AV. Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides. FASEB J, 31, 3467-3483 (2017)
  • Nasu, K., Yamaguchi K., Takanashi, T., Tamai, K., Sato, I., Ine, S., Sasaki, O., Satoh, K., Tanaka, N., Tanaka, Y., Fukushima, T., Harigae, H., and Sugamura, K. Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells. Cancer Sci, 108, 435-443 (2017).
  • Shiroki, T, Yokoyama, M, Tanuma, N, Maejima, R, Tamai, K, Yamaguchi, K, Oikawa, T, Noguchi, T, Miura, K, Fujiya, T, Shima, H, Sato, I, Murata-Kamiya, N, Hatakeyama, M, Iijima, K, Shimosegawa, T, and Satoh, K Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism. Cancer Sci. 108, 931-940 (2017).

2016年

  • *Koshiba, S, Motoike, I, Kojima, K, Hasegawa, T, Shirota, M, Saito, T, Saigusa, D, Danjoh, I, Katsuoka, F, Ogishima, S, Kawai, Y, Yamaguchi-Kabata, Y, Sakurai, M, Hirano, S, Nakata, J, Motohashi, H, Hozawa, A, Kuriyama, S, Minegishi, N, Nagasaki, M, Takai-Igarashi, T, Fuse, N, Kiyomoto, H, Sugawara, J, Suzuki, Y, Kure, S, Yaegashi, N, Tanabe, O, Kinoshita, K, Yasuda, J and Yamamoto, M, The structural origin of metabolic quantitative diversity, Sci Rep, 6, 31463, 2016
  • Kohda, M, Tokuzawa, Y, Kishita, Y, Nyuzuki, H, Moriyama, Y, Mizuno, Y, Hirata, T, Yatsuka, Y, Yamashita-Sugahara, Y, Nakachi, Y, Kato, H, Okuda, A, Tamaru, S, Borna, NN, Banshoya, K, Aigaki, T, Sato-Miyata, Y, Ohnuma, K, Suzuki, T, Nagao, A, Maehata, H, Matsuda, F, Higasa, K, Nagasaki, M, Yasuda, J, Yamamoto, M, Fushimi, T, Shimura, M, Kaiho-Ichimoto, K, Harashima, H, Yamazaki, T, Mori, M, Murayama, K, Ohtake, A and Okazaki, Y, A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies, PLoS Genet, 12, 1, e1005679, 2016
  • Kuriyama, S, Yaegashi, N, Nagami, F, Arai, T, Kawaguchi, Y, Osumi, N, Sakaida, M, Suzuki, Y, Nakayama, K, Hashizume, H, Tamiya, G, Kawame, H, Suzuki, K, Hozawa, A, Nakaya, N, Kikuya, M, Metoki, H, Tsuji, I, Fuse, N, Kiyomoto, H, Sugawara, J, Tsuboi, A, Egawa, S, Ito, K, Chida, K, Ishii, T, Tomita, H, Taki, Y, Minegishi, N, Ishii, N, Yasuda, J, Igarashi, K, Shimizu, R, Nagasaki, M, Koshiba, S, Kinoshita, K, Ogishima, S, Takai-Igarashi, T, Tominaga, T, Tanabe, O, Ohuchi, N, Shimosegawa, T, Kure, S, Tanaka, H, Ito, S, Hitomi, J, Tanno, K, Nakamura, M, Ogasawara, K, Kobayashi, S, Sakata, K, Satoh, M, Shimizu, A, Sasaki, M, Endo, R, Sobue, K, Tohoku Medical Megabank Project Study Group, T and Yamamoto, M, The Tohoku Medical Megabank Project: Design and Mission, J Epidemiol, 26, 9, 493-511, 2016
  • Saigusa, D, Okamura, Y, Motoike, IN, Katoh, Y, Kurosawa, Y, Saijyo, R, Koshiba, S, Yasuda, J, Motohashi, H, Sugawara, J, Tanabe, O, Kinoshita, K and Yamamoto, M, Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery, PLoS One, 11, 8, e0160555, 2016Takahashi S, Satoh D, Hayashi M, Takahashi K, Yamaguchi K, Nakamura T, Koshino H. Total synthesis of the proposed structure for aromin and its structural revision. J Org Chem, 81, 11222-11234 (2016).
  • Yamaguchi K, Takanashi T, Nasu K, Tamai K, Mochizuki M, Satoh I, Ine S, Sasaki O, Satoh K, Tanaka N, Harigae H, Sugamura K. Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation. Cancer Sci, 107, 638-643 (2016).
  • Mochizuki M, Tamai K, Imai T, Sugawara S, Ogama N, Nakamura M, Matsuura K, Yamaguchi K, Satoh K, Sato I, Motohashi H, Sugamura K, Tanaka N. CD271 regulates the proliferation and motility of hypopharyngeal cancer cells. Sci Rep, 6, 30707 (2016).

2015年

  • *Nagasaki, M, Yasuda, J, Katsuoka, F, Nariai, N, Kojima, K, Kawai, Y, Yamaguchi-Kabata, Y, Yokozawa, J, Danjoh, I, Saito, S, Sato, Y, Mimori, T, Tsuda, K, Saito, R, Pan, X, Nishikawa, S, Ito, S, Kuroki, Y, Tanabe, O, Fuse, N, Kuriyama, S, Kiyomoto, H, Hozawa, A, Minegishi, N, Douglas Engel, J, Kinoshita, K, Kure, S, Yaegashi, N, To, MJRPP and Yamamoto, M, Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals, Nat Commun, 6, 8018, 2015
  • Kawai, Y, Mimori, T, Kojima, K, Nariai, N, Danjoh, I, Saito, R, Yasuda, J, Yamamoto, M and Nagasaki, M, Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals, J Hum Genet, 60, 10, 581-7, 2015
  • Nariai, N, Kojima, K, Saito, S, Mimori, T, Sato, Y, Kawai, Y, Yamaguchi-Kabata, Y, Yasuda, J and Nagasaki, M, HLA-VBSeq: accurate HLA typing at full resolution from whole-genome sequencing data, BMC Genomics, 16 Suppl 2, S7, 2015
  • Yamaguchi-Kabata, Y, Nariai, N, Kawai, Y, Sato, Y, Kojima, K, Tateno, M, Katsuoka, F, Yasuda, J, Yamamoto, M and Nagasaki, M, iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing, Hum Genome Var, 2, 15050, 2015
  • Abue M, Yokoyama M, Shibuya R, Tamai K, Yamaguchi K, Sato I, Tanaka N, Hamada S, Shimosegawa T, Sugamura K, Satoh K. Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol, 46, 539-547 (2015).
  • Kuramitsu M, Okuma K, Yamagishi M, Yamochi T, Firouzi S, Momose H, Mizukami T, Takizawa K, Araki K, Sugamura K, Yamaguchi K, Watanabe T, Hamaguchi I. Identification of TL-Om1, an adult T-cell leukemia (ATL) cell line, as reference material for quantitative PCR for human T-lymphotropic virus 1. J Clin Microbiol, 53, 587-596 (2015).
  • Miyagi T, Takahashi K, Shiozaki K, Yamaguchi K, Hosono M. Plasma membrane-associated sialidase confers cancer initiation, promotion and progression. Adv Exp Med Biol, 842, 139-145 (2015).
  • Hata K, Tochigi T, Sato I, Kawamura S, Shiozaki K, Wada T, Takahashi K, Moriya S, Yamaguchi K, Hosono M, Miyagi T. Increased sialidase activity in serum of cancer patients: Identification of sialidase and inhibitor activities in human serum. Cancer Sci, 106, 383-389 (2015).
  • Shiozaki K, Takahashi K, Hosono M, Yamaguchi K, Hata K, Shiozaki M, Bassi R, Prinetti A, Sonnino S, Nitta K, Miyagi T. Phosphatidic acid-mediated activation and translocation to the cell surface of sialidase NEU3, promoting signaling for cell migration. FASEB J, 29, 2099-2111 (2015).
  • Takahashi K, Hosono M, Sato I, Hata K, Wada T, Yamaguchi K, Nitta K, Shima H, Miyagi T. Sialidase NEU3 contributes neoplastic potential on colon cancer cells as a key modulator of gangliosides by regulating Wnt signaling. Int J Cancer, 137, 1560-1573 (2015).
  • Yamamoto K, Takahashi K, Shiozaki K, Yamaguchi K, Moriya S, Hosono M, Shima H, Miyagi T. Potentiation of epidermal growth factor-mediated oncogenic transformation by sialidase NEU3 leading to Src activation. PLoS One, 10, e0120578 (2015).

2014年

  • *Katsuoka, F, Yokozawa, J, Tsuda, K, Ito, S, Pan, X, Nagasaki, M, Yasuda, J and Yamamoto, M, An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer, Anal Biochem, 466, 27-9, 2014
  • *Motoike, IN, Matsumoto, M, Danjoh, I, Katsuoka, F, Kojima, K, Nariai, N, Sato, Y, Yamaguchi-Kabata, Y, Ito, S, Kudo, H, Nishijima, I, Nishikawa, S, Pan, X, Saito, R, Saito, S, Saito, T, Shirota, M, Tsuda, K, Yokozawa, J, Igarashi, K, Minegishi, N, Tanabe, O, Fuse, N, Nagasaki, M, Kinoshita, K, Yasuda, J and Yamamoto, M, Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population, BMC Genomics, 15, 673, 2014
  • Nagata T, Murata K, Murata R, Sun SL, Saito Y, Yamaga S, Tanaka N, Tamai K, Moriya K, Kasai N, Sugamura K, Ishii N. Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells. Biochem Biophys Res Commun, 443, 351-356 (2014).
  • Tamai K, Nakamura M, Mizuma M, Mochizuki M, Yokoyama M, Endo H, Yamaguchi K, Nakagawa T, Shiina M, Unno M, Muramoto K, Sato I, Satoh K, Sugamura K, Tanaka N. Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma. Cancer Sci, 105, 667-674 (2014).
  • Yamaki S, Ine S, Kawabe T, Okuyama Y, Suzuki N, Soroosh P, Mousavi SF, Nagashima H, Sun SL, So T, Sasaki T, Harigae H, Sugamura K, Kudo H, Wada M, Nio M, Ishii N. OX40 and IL-7 play synergistic roles in the homeostatic proliferation of effector memory CD4+ T cells. Eur J Immunol, 44, 3015-3025 (2014).
  • Kojima K, Amano Y, Yoshino K, Tanaka N, Sugamura K, Takeshita T. ESCRT-0 protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is targeted to endosomes independently of signal-transducing adaptor molecule (STAM) and the complex formation with STAM promotes its endosomal dissociation. J Biol Chem, 289, 33296-33310 (2014).

2013年

  • Imai T, Tamai K, Oizumi S, Oyama K, Yamaguchi K, Sato I, Satoh K, Matsuura K, Saijo S, Sugamura K, Tanaka N. CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer. PLoS ONE, 8, e62002 (2013).
  • Horino S, Uchiyama T, So T, Nagashima H, Sun SL, Sato M, Asao A, Haji Y, Sasahara Y, Candotti F, Tsuchiya S, Kure S, Sugamura K, Ishii N. Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector. PLoS One, 8, e71594 (2013).
  • Endo H, Shiroki T, Nakagawa T, Yokoyama M, Tamai K, Yamanami H, Fujiya T, Sato I, Yamaguchi K, Tanaka N, Iijima K, Shimosegawa T, Sugamura K, Satoh K. Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer. PLoS One, 8, e77070 (2013).
  • Shiozaki K, Takeshita K, Ikeda M, Ikeda A, Harasaki Y, Komatsu M, Yamada S, Yamaguchi K, Miyagi T. Molecular cloning and biochemical characterization of two novel Neu3 sialidases, neu3a and neu3b, from medaka (Oryzias latipes). Biochimie, 95, 280-289 (2013).

2012年

  • Koseki K, Wada T, Hosono M, Hata K, Yamaguchi K, Nitta K, Miyagi T. Human cytosolic sialidase NEU2-low general tissue expression but involvementin PC-3 prostate cancer cell survival. Biochem Biophys Res Commun, 428, 142-149 (2012).
  • Miyagi T, Takahashi K, Moriya S, Hata K, Yamamoto K, Wada T, Yamaguchi K, Shiozaki K. Altered expression of sialidases in human cancer. Adv Exp Med Biol, 749, 257-267 (2012).
  • Yamaguchi K, Shiozaki K, Moriya S, Koseki K, Wada T, Tateno H, Sato I, Asano M, Iwakura Y, Miyagi T. Reduced susceptibility to colitis-associated colon carcinogenesis in mice lacking plasma membrane-associated sialidase. PLoS One, 7, e41132 (2012).
  • Miyagi T, Yamaguchi K. Mammalian sialidases: Physiological and pathological roles in cellular functions. Glycobiology, 22, 880-896 (2012).
  • Takahashi K, Mitoma J, Hosono M, Shiozaki K, Sato C, Yamaguchi K, Kitajima K, Higashi H, Nitta K, Shima H, Miyagi T. Sialidase NEU4 hydrolyzes polysialic acids of neural cell adhesion molecules and negatively regulates neurite formation by hippocampal neurons. J Biol Chem, 287, 14816-14826 (2012).
  • Suzuki T, Yamaguchi K. Structure, Biosynthesis and Function Sialic Acid Glycoconjugates in Health and Disease, 2012, 188-208 Joe Tiralongo and Ivan Martinez-Duncker (Eds) 2012 Bentham Science Publishers CHAPTER 6 Mammalian Sialidases
  • Tamai K, Shiina M, Tanaka N, Nakano T, Yamamoto A, Kondo Y, Kakazu E, Inoue J, Fukushima K, Sano K, Ueno Y, Shimosegawa T, Sugamura K. Regulation of hepatitis C virus secretion by the Hrs-dependent exosomal pathway. Virology, 422, 377-385 (2012).

2011年

  • *Yokoo, H, Yasuda, J, Nakanishi, K, Chuma, M, Kamiyama, T, Todo, S, Hirohashi, S and Sakamoto, M, Clinicopathological significance of nuclear factor-kappaB activation in hepatocellular carcinoma, Hepatol Res, 41, 3, 240-9, 2011
  • Kawamura S, Sato I, Wada T, Yamaguchi K, Li Y, Li D, Zhao X, Ueno S, Aoki H, Tochigi T, Kuwahara M, Kitamura T, Takahashi K, Moriya S, Miyagi T. Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling. Cell Death Differ, 19, 170-179, (2011 Jun 17).
  • Suzuki S, Tamai K, Watanabe M, Kyuuma M, Ono M, Sugamura K, Tanaka N. AMSH is required to degrade ubiquitinated proteins in the central nervous system. Biochem Biophys Res Commun, 408, 582-588, (2011).
  • Amano Y, Yamashita Y, Kojima K, Yoshino K, Tanaka N, Sugamura K, Takeshita T. Hrs Recognizes a Hydrophobic Amino Acid Cluster in Cytokine Receptors during Ubiquitin-independent Endosomal Sorting. J Biol Chem, 286, 15458-72, (2011).
  • 山口壹範, 宮城妙子 シアリダーゼ、生物機能モデルと新しいリソースリサーチツール, pp340-345, エルアイシー, 2011
  • Shiozaki K, Yamaguchi K, Takahashi K, Moriya S, Miyagi T. Regulation of sialyl lewis antigen expression in colon cancer cells by sialidase NEU4. J Biol Chem, 286, 21052-21061, (2011).

2010年

  • *Forrest, AR, Kanamori-Katayama, M, Tomaru, Y, Lassmann, T, Ninomiya, N, Takahashi, Y, de Hoon, MJ, Kubosaki, A, Kaiho, A, Suzuki, M, Yasuda, J, Kawai, J, Hayashizaki, Y, Hume, DA and Suzuki, H, Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation, Leukemia, 24, 2, 460-6, 2010
  • *Sudo, K, Yasuda, J and Nakamura, Y, Gene expression profiles of cryopreserved CD34(+) human umbilical cord blood cells are related to their bone marrow reconstitution abilities in mouse xenografts, Biochem Biophys Res Commun, 397, 4, 697-705, 2010
  • Tamai K, Tanaka N, Nakano T, Kakazu E, Kondo Y, Inoue J, Shiina M, Fukushima K, Hoshino T, Sano K, Ueno Y, Shimosegawa T, Sugamura K. Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem Biophys Res Commun, 27, 399(3), 384-90, (2010).
  • Yamaguchi K, Koseki K, Shiozaki M, Shimada Y, Wada T, Miyagi T. Regulation of plasma-membrane-associated sialidase NEU3 gene by Sp1/Sp3 transcription factors. Biochem J, 430, 107-117, (2010).
  • Katoh S, Maeda S, Fukuoka H, Wada T, Moriya S, Mori A, Yamaguchi K, Senda S, Miyagi T. A crucial role of sialidase neu1 in hyaluronan receptor function of CD44 in T helper type 2-mediated airway inflammation of murine acute asthmatic model. Clin Exp Immunol, 161, 233-241, (2010).

2009年

  • Shiozaki K, Yamaguchi K, Sato I, Miyagi T. Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice. Cancer Sci, 100, 588-594, (2009).
  • Shiozaki K, Koseki K, Yamaguchi K, Shiozaki M, Narimatsu H, Miyagi T. Developmental change of sialidase neu4 expression in murine brain and its involvement in the regulation of neuronal cell differentiation. J Biol Chem, 284, 21157-21164, (2009).
  • Uemura T, Shiozaki K, Yamaguchi K, Miyazaki S, Satomi S, Kato K, Sakuraba H, Miyagi T. Contribution of sialidase NEU1 to suppression of metastasis of human colon cancer cells through desialylation of integrin beta4. Oncogene, 28, 1218-1229, (2009).

2008年

  • Kawaji, H, Nakamura, M, Takahashi, Y, Sandelin, A, Katayama, S, Fukuda, S, Daub, CO, Kai, C, Kawai, J, Yasuda, J, Carninci, P and Hayashizaki, Y, Hidden layers of human small RNAs, BMC Genomics, 9, 157, 2008
  • Yasuda, J and Hayashizaki, Y, The RNA continent, Adv Cancer Res, 99, 77-112, 2008 Carninci, P, Yasuda, J and Hayashizaki, Y, Multifaceted mammalian transcriptome, Curr Opin Cell Biol, 20, 3, 274-80, 2008
  • Tamai K, Toyoshima M, Tanaka N, Yamamoto N, Owada Y, Kiyonari H, Murata K, Ueno Y, Ono M, Shimosegawa T, Yaegashi N, Watanabe M, and Sugamura K. Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration. Am.J.Pathol, 173, 1806-17, (2008).
  • Tanaka Y, Tanaka, N, Saeki Y, Tanaka K, Murakami M, Hirano T, Ishii N, Sugamura K. c-Cbl-dependent Monoubiquitination and Lysosomal Degradation of gp130. Mol. Cell. Biol, 28, 4805-4818, (2008).
  • Tanaka N, Kyuuma M, Sugamura K. Endosomal sorting complex required for transport proteins in cancer pathogenesis, vesicular transport, and non-endosomal functions. Cancer Sci, 99, 1293-303, (2008).
  • Yamashita Y, Kojima K, Tsukahara T, Agawa H, Yamada K, Amano Y, Kurotori N, Tanaka N, Sugamura K, Takeshita T. Ubiquitin-independent binding of Hrs mediates endosomal sorting of the interleukin-2 receptor β-chain. J. Cell. Sci, 121, 1727-38, (2008).
  • Hata K, Koseki K, Yamaguchi K, Moriya S, Suzuki Y, Yingsakmongkon S, Hirai G, Sodeoka M, von Itzstein M, Miyagi T. Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob Agents Chemother, 52, 3484-3491, (2008).
  • Miyagi T, Wada T, Yamaguchi K. Roles of plasma membrane-associated sialidase NEU3 in human cancers. Biochim Biophys Acta, 1780, 532-537, (2008).
  • Miyagi T, Wada T, Yamaguchi K, Hata K, Shiozaki K. Plasma membrane-associated sialidase as a crucial regulator of transmembrane signalling. J Biochem, 144, 279-285, (2008).
  • Miyagi T, Wada T, Yamaguchi K, Shiozaki K, Sato I, Kakugawa Y, Yamanami H, Fujiya T. Human sialidase as a cancer marker. Proteomics, 8, 3303-3311 (2008).
  • Yamaguchi K, Miyagi T. Function of NEU3 sialidase in membrane microdomains. Tanpakushitsu Kakusan Koso, 53(12 Suppl), 1570-1574, (2008, Sep).

2007年

  • Yasuda, J and Ichikawa, H, Mammalian Nemo-like kinase enhances beta-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells, Proc Jpn Acad Ser B Phys Biol Sci, 83, 1, 16-25, 2007
  • Toyoshima M, Tanaka N, Aoki J, Tanaka Y, Murata K, Kyuuma M, Kobayashi H, Ishii N, Yaegashi N, Sugamura K. Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs: its regulatory role on E-cadherin and beta-catenin. Cancer Res, 67, 5162-71, (2007).
  • Onoda T, Rahman M, Nara H, Araki A, Makabe K, Tsumoto K, Kumagai I, Kudo T, Ishii N, Tanaka N, Sugamura K, Hayasaka K, Asao H. Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4+ T cell subsets. Int Immunol, 10, 1191-9, (2007).
  • Tamai,K, Tanaka, N., Nara, A, Yamamoto,A Nakagawa, I., Yoshimori, T. Ueno, U, Shimosegawa, T, and Sugamura K. Role of Hrs in Maturation of Autophagosomes in Mammalian Cell. Biochem Biophys Res Commun, 360, 721-7, (2007).
  • Inoue Y, Tanaka N, Tanaka Y, Inoue S, Morita K, Min Z, Hattori T, Sugamura K. Clathrin-dependent Entry of SARS Coronavirus into Target Cells Expressing Cytoplasmic Tail-deleted ACE2. J Virol, 81, 8722-9, (2007).
  • Kyuuma M, Kikuchi K, Kojima K, Sugawara Y, Sato M, Mano N, Goto J, Takeshita T, Yamamoto A, Sugamura K, Tanaka N. AMSH, an ESCRT-III associated enzyme, deubiquitinates cargo on MVB/late endosomes. Cell Struct Funct, 31, 159-72, (2007).
  • Yamanami H, Shiozaki K, Wada T, Yamaguchi K, Uemura T, Kakugawa Y, Hujiya T, Miyagi T. Down-regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers. Cancer Sci, 98, 299-307, (2007).
  • Miyagi T, Yamaguchi K. Sialic acids. In: Kamerling JP, Boons G-J, editors. Comprehensive Glycoscience : from chemistry to systems biology. Amsterdam; Boston: Elsevier; 2007. p. 297-323.
  • Yoshizumi S, Suzuki S, Hirai M, Hinokio Y, Yamada T, Yamada T, Tsunoda U, Aburatani H, Yamaguchi K, Miyagi T, Oka Y. Increased hepatic expression of ganglioside-specific sialidase, NEU3, improves insulin sensitivity and glucose tolerance in mice. Metabolism, 56, 420-429, (2007).
  • Wada T, Hata K, Yamaguchi K, Shiozaki K, Koseki K, Moriya S, Miyagi T. A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells. Oncogene, 26, 2483-2490, (2007).

2006年

  • Nakashima A, Tanaka N, Tamai K, Kyuuma M, Ishikawa Y, Sato H, Yoshimori T, Saito S, Sugamura K. Survival of parvovirus B19-infected cells by cellular autophagy. Virology, 5, 349, 254-63, (2006).
  • Ishikawa Y, Tanaka N, Murakami K, Uchiyama T, Kumaki S, Tsuchiya S, Kugoh H, Oshimura M, Calos MP, Sugamura K. Phage phiC31 integrase-mediated genomic integration of the common cytokine receptor gamma chain in human T-cell lines. J Gene Med, 8, 646-653, (2006).
  • Uchiyama T, Kumaki S, Ishikawa Y, Onodera M, Sato M, Du W, Sasahara Y, Tanaka N, Sugamura K, Tsuchiya S. Application of HSVtk suicide gene to X-SCID gene therapy: ganciclovir treatment offsets gene corrected X-SCID B cells. Biochem Biophys Res Commun, 341(2), 391-8, (2006).
  • Yamaguchi K, Hata K, Wada T, Moriya S, Miyagi T. Epidermal growth factor-induced mobilization of a ganglioside-specific sialidase (NEU3) to membrane ruffles. Biochem Biophys Res Commun, 346, 484-490, (2006).
  • Kato K, Shiga K, Yamaguchi K, Hata K, Kobayashi T, Miyazaki K, Saijo S, Miyagi T. Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling. Biochem J, 394, 647-656, (2006).
  • Ueno S, Saito S, Wada T, Yamaguchi K, Satoh M, Arai Y, Miyagi T. Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility. J Biol Chem, 281, 7756-7764, (2006).

2005年

  • Niinuma A, Higuchi M, Takahashi M, Oie M, Tanaka Y, Gejyo F, Tanaka N, Sugamura K, Xie L, Green PL, Fujii M. Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus. J Virol, 79, 11925-34, (2005).
  • Kobayashi H, Tanaka N, Asao H, Miura S, Kyuuma M, Semura K, Ishii N, Sugamura K. Hrs, a mammalian master molecule in vesicular transport and protein sorting, suppresses the degradation of ESCRT proteins signal transducing adaptor molecule 1 and 2. J Biol Chem, 280, 10468-77, (2005).
  • Yamaguchi K, Hata K, Koseki K, Shiozaki K, Akita H, Wada T, Moriya S, Miyagi T. Evidence for mitochondrial localization of a novel human sialidase (NEU4). Biochem J, 390, 85-93, (2005).

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