がん治療標的分子は血漿にUbiquitousか

• Project/Area Number: 21659149
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Laboratory medicine
• Research Institution: Nagasaki University
• Principal Investigator: 上平 憲 長崎大学, 医歯薬学総合研究科, 教授 (80108290)
• Co-Investigator(Kenkyū-buntansha): 山田 恭暉 長崎大学, 医歯薬学総合研究科, 准教授 (60145232) ; 長谷川 寛雄 長崎大学, 医歯薬学総合研究科, 助教 (00398166)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2010: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2009: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: 癌治療標的 / microRNA / miR155 / 個別化治療 / がんシグナル / 癌治療標的分子 / EZH2 / 血漿核酸 / 個性化治療

Research Abstract

ここ数年の間に、造血器腫瘍・固形がんを中心に分子標的療法や個別化医療が徐々に導入されつつある。その基本は、当然のことながら分子標的を確認することに始まる。次に、germ-line検査にて体質個性を調べてこごの患者にベストのオーダーメイド医療を行うことになる。しかし、SNP等の個性検査は必ずしも発病後に調べなくても、いつ・どんな制度で行うか緊急性も考慮して国民のコンセンサスを得ておくことも大事である。疾病の側の体細胞変異などの治療標的は、白血病を除けば通常固形がんにおいては、検査サンプルの採取において、侵襲性をともなうことが多い点も問題点の一つである。そこで、昨年度は、今oncogensis分野のトピックスのひとつである血漿中でも安定的なmicroRNAが目的の代理マーカーになり得るか否かをpilot的に検討した。
第1に少なくとも細胞内において分子標的をmicroRNAと言う単なる一分子で識別できるのか。また、細胞内と血漿中のmicroRNAがubiquitusとなり得るか否かを検討した。その為に、最初に、腫瘍細胞と血漿中の間にmicroRNAの濃度にdiscrepancyがないのかを検討することが本ideaの基本成否の鍵となると思われたのでこの点はmicoRNA,RT-PCR,定量real-time qPCRで慎重に検討した。今回の検討では、細胞内では高値であったmiR155が血漿中ではむしろ低く、むしろ細胞内ではdown-regulated microRNAが血漿中では優位に二者間で差が観察されおのが少なからず存在することがわかった。
従って、血漿中のmiR-RNAの場合、高値のみならず、低値例にも注目し、いくつかのmiRを組み合わせてscreeningすることで可成りの分子標的ないしがん細胞の体細胞変異が調べられることが示唆された。今後は、この戦略に基づいて一つ一つ検証して一日も早い実用化を希望している。

Research Products

• [Journal Article] Trends in HTLV-I prevalence and incidence of adult T-cell leukemia/lymphoma in Nagasaki, Japan. (2010)
  • Author(s): Koga Y, Iwanaga M, Soda M, Inokuchi N, Sasaki D, Hasegawa H, Yanagihara K, Yamaguchi K, Kamihira S, Yamada Y
  • Journal Title: J Med Virol 2010 Volume: 82(4) Pages: 668-674
  • Peer Reviewed
• [Journal Article] CADMI interacts with Tiam1 and promotes invasive phenotype of human T-cell leukemia virus type I-transformed cells and adult T-cell leukemia cells. (2010)
  • Author(s): Masuda M, Maruyama T, Ohta T, Ito A, Hayashi T, Tsukasaki K, Kamihira S, Yamaoka S, Hoshino H, Yoshida T, Watanabe T, Stanbridge EJ, Murakami Y
  • Journal Title: J Biol Chem Volume: 285(20) Pages: 15511-22
  • Peer Reviewed
• [Journal Article] First Japanese patient treated with parathyroid hormone peptide immunization for refractory hypercalcemia caused by metastatic parathyroid carcinoma. (2010)
  • Author(s): Horie I, Ando T, Inokuchi N, Mihara Y, Miura S, Imaizumi M, Usa T, Kinoshita N, Sekine I, Kamihara S, Eguchi K
  • Journal Title: Endocr J Volume: 57(4) Pages: 287-92
  • Peer Reviewed
• [Journal Article] Long-term study of indolent adult T-cell leukemia-lymphoma. (2010)
  • Author(s): Takasaki Y, Iwanaga M, Imaizumi Y, Tawara M, Joh T, Kohno T, Yamada Y, Kamihira S, Ikeda S, Miyazaki Y, Tomonaga M, Tsukasaki K
  • Journal Title: Blood Volume: 115(22) Pages: 4337-43
  • Peer Reviewed
• [Journal Article] Intra- and inter-laboratory variability in human T-cell leukemia virus type-1 proviral load quantification using real-time polymerase chain reaction assays : a multi-center study (2010)
  • Author(s): Kamihira S, Yamano Y, Iwanaga M, Sasaki D, Satake M, Okayama A, Umeki K, Kubota R, Izumo S, Yamaguchi K, Watanabe T
  • Journal Title: Cancer Sci Volume: 101(11) Pages: 2361-7
  • NAID: 10027833409
  • Peer Reviewed
• [Journal Article] HTLV-1 proviral load and disease progression in asymptomatic HTLV-1 carriers : A nationwide prospective Study in Japan (2010)
  • Author(s): Iwanaga M, Watanabe T, Utsunomiya A, Okayama A, Uchimaru K, Koh KR, Ogata M, Kikuchi H, Sagara Y, Uozumi K, Mochizuki M, Tsukasaki K, Saburi Y.Yamamura M, Tanaka J, Moriuchi Y, Hino S, Kamihira S, Yamaguchi K
  • Journal Title: Blood Volume: 116(8) Pages: 1211-9
  • Peer Reviewed
• [Journal Article] Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. (2010)
  • Author(s): Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, Miyake K, Maeda T, Kamihira S, Miyachi Y, Uchiyama T
  • Journal Title: Blood Volume: 117(2) Pages: 500-9
  • Peer Reviewed
• [Journal Article] Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. (2010)
  • Author(s): Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K, Yamada Y, Hanada S, Tamura K, Nakamura S, Inagaki H, Ohshima K, Kiyoi H, Ishida T, Matsushima K, Akinaga S, Ogura M, Tomonaga M, Ueda R
  • Journal Title: J Clin Oncol Volume: 28 Pages: 1591-1598
  • Peer Reviewed
• [Journal Article] Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells. (2009)
  • Author(s): Hasegawa H, Yamada Y, Iha H, Tsukasaki K, Nagai K, Atogami S, Sugahara K, Tsuruda K, Ishizaki A, Kamihira S.
  • Journal Title: Leukemia 23(11) Pages: 2090-2101
  • NAID: 120006983888
  • Peer Reviewed
• [Journal Article] Aberrant p53 protein expression and function in a panel of hematopoietic cell lines with different p53 mutations (2009)
  • Author(s): Kamihira S, Terada C, Sasaki D, Yanagihara K, Tsukasaki K, Hasegawa H, Yamada Y.
  • Journal Title: Eur J Haematol 82(4) Pages: 301-307
  • Peer Reviewed
• [Journal Article] Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors. (2009)
  • Author(s): Iwanaga M, Tagawa M, Tsukasaki K, Matsuo T, Yokota K, Miyazaki Y, Fukushima T, Hata T, Imaizumi Y, Imanishi D, Taguchi J, Momita S, Kamihira S, Tomonaga M.
  • Journal Title: Blood. 113(8) Pages: 1639-50
  • NAID: 120006982803
  • Peer Reviewed
• [Journal Article] A novel role of serum cytochrome c as a tumor marker in patients with operable cancer. (2009)
  • Author(s): Osaka A, Hasegawa H, Yamada Y, Yanagihara K, Hayashi T, Mine M, Aoyama M, Sawada T, Kamihira S
  • Journal Title: J Cancer Res Clin Oncol 135(3) Pages: 371-7
  • NAID: 120006983957
  • Peer Reviewed
• [Journal Article] Elevation of serum KL-6 glycoprotein or surfactant protein-D in adult T-cell leukemia with distinct pulmonary complications. (2009)
  • Author(s): Osaka A, Yanagihara K, Yamada Y, Hasegawa H, Inokuchi N, Hayashi T, Komoda M, Nakamura S, Aoyama M, Sawada T, Kamihira S
  • Journal Title: Tohoku J Exp Med 218(2) Pages: 99-105
  • NAID: 10025106239
  • Peer Reviewed
• [Journal Article] High-resolution melting analysis for a reliable and two-step scanning of mutations in the tyrosine kinase domain of the chimerical bcr-abl gene. (2009)
  • Author(s): Doi Y, Sasaki D, Terada C, Mori S, Tsuruda K, Matsuo E, Miyazaki Y, Nagai K, Hasegawa H, Yanagihara K, Yamada Y, Kamihira S
  • Journal Title: Int J Hematol 90(1) Pages: 37-43
  • NAID: 10025162376
  • Peer Reviewed
• [Journal Article] Serum cytochrome c to indicate the extent of ongoing tumor cell death. (2009)
  • Author(s): Osaka A, Hasegawa H, Tsuruda K, Inokuchi N, Yanagihara K, Yamada Y, Aoyama M, Sawada T, Kamihira S
  • Journal Title: Int J Lab Hematol 31(3) Pages: 307-14
  • Peer Reviewed
• [Presentation] 成人T細胞白血病におけるmicroRNAの発現 (2011)
  • Author(s): 石原香織
  • Organizer: 日本臨床検査学会九州支部総会
  • Place of Presentation: 福岡
  • Year and Date: 2011-02-12
• [Presentation] Overexpression of anhancer of zeste homolog 2 with trimethylation of lyaine 27 on histone H3 in ATL as a target for epigenetic therapy (2010)
  • Author(s): 佐々木大介
  • Organizer: ASH
  • Place of Presentation: 米国
  • Year and Date: 2010-12-20
• [Presentation] The Overexpression of Enhancer of Zeste Homologue 2 Is Associated withTumor Proliferation and Aggressive Behavior in Adult T-Cell Leukemia/Lymphoma. (2009)
  • Author(s): Daisuke Sasaki, Shimeru Kamihira
  • Organizer: ASH American Annual Meeting
  • Place of Presentation: USA, New Orins
• [Presentation] 自然の実験系ATLに学ぶ臨床化 (2009)
  • Author(s): 上平憲
  • Organizer: 第49回日本臨床化学会学術集会
  • Place of Presentation: 長崎市
• [Book] 臨床検査ガイド2009-2010 (2009)
  • Author(s): 上平憲
  • Total Pages: 6
  • Publisher: 文光堂(東京)