A role of microRNA-mediated regulatory mechanism of WT1 in oncogenesis

• Project/Area Number: 25460685
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Osaka University
• Principal Investigator: TATSUMI NAOYA 大阪大学, 医学(系)研究科(研究院), 寄附講座助教 (60512960)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: microRNA / WT1遺伝子 / 白血病 / Zbtb7a遺伝子 / 肺癌 / WT1 / ノックアウトマウス / アポトーシス / 細胞周期

Outline of Final Research Achievements

In the present study, we showed that knockout mice for miR-125a, which directly targets and suppresses the expression of WT1 gene, developed myeloproliferative disorder (MPD) characterized by expansion of myeloid cells. Furthermore, the incidence and severity of MPD were lower in miR-125a (-/-) mice than in miR-125a (+/-) mice, indicating the operation of compensatory mechanisms for the complete loss of miR-125a. MiR-486 was occasionally induced in compete loss of miR-125a and, resulting in the cancellation of MPD occurrence. Moreover, we showed that Zbtb7a was a direct target for miR-125a and that miR-125a played an important role in oncogenesis through the regulation of two oncogenes, WT1 and Zbtb7a.

Research Products

• [Journal Article] Induction of eEF2-specific antitumor CTL responses in vivo by vaccination with eEF2-derived 9mer-peptides (2016)
  • Author(s): Nakajima H, Murakami Y, Morii E, Akao T, Tatsumi N, Odajima S, Fukuda M, Machitani T, Iwai M, Kawata S, Hojo N, Oka Y, Sugiyama H, Oji Y
  • Journal Title: Oncol Rep Volume: 35 Issue: 4 Pages: 1959-1966
  • DOI: 10.3892/or.2016.4589
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An essential role of the avidity of T-cell receptor in differentiation of self-antigen-reactive CD8+ T cells (2016)
  • Author(s): Kondo K, Fujiki F, Nakajima H, Yatsukawa E, Morimoto S, Tatsumi N, Nishida S, Nakata J, Oka Y, Tsuboi A, Hosen N, Oji Y, Sugiyama H
  • Journal Title: Journal of Immunotherapy Volume: 39 Issue: 3 Pages: 127-139
  • DOI: 10.1097/cji.0000000000000114
  • Peer Reviewed / Open Access
• [Journal Article] Glycosylation Status of CD43 Protein Is Associated with Resistance of Leukemia Cells to CTL-Mediated Cytolysis. (2016)
  • Author(s): Hasegawa K, Tanaka S, Fujiki F, Morimoto S, Nakano K, Kinoshita H, Okumura A, Fujioka Y, Urakawa R, Nakajima H, Tatsumi N, Nakata J, Takashima S, Nishida S, Tsuboi A, Oka Y, Oji Y, Miyoshi E, Hirata T, Kumanogoh A, Sugiyama H, Hosen N.
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0152326-e0152326
  • DOI: 10.1371/journal.pone.0152326
  • Peer Reviewed / Open Access
• [Journal Article] A Zbtb7a proto-oncogene as a novel target for miR-125a. (2016)
  • Author(s): Hojo N, Tatsumi N, Moriguchi N, Matsumura A, Morimoto S, Nakata J, Fujiki F, Nishida S, Nakajima H, Tsuboi A, Oka Y, Hosen N, Hayashi S, Sugiyama H, Oji Y.
  • Journal Title: Molecular Carcinogenesis Volume: - Issue: 12 Pages: 1-9
  • DOI: 10.1002/mc.22446
  • Peer Reviewed / Open Access
• [Journal Article] Transduction of a Novel HLA-DRB1*04:05-restricted, WT1-specific TCR Gene into Human CD4+ T Cells Confers Killing Activity Against Human Leukemia Cells (2015)
  • Author(s): Katsuhara A, Fujiki F, Aoyama N, Tanii S, Morimoto S, Oka Y, Tsuboi A, Nakajima H, Kondo K, Tatsumi N, Nakata J, Nakae Y, Takashima S, Nishida S, Hosen N, Sogo S, Oji Y, Sugiyama H
  • Journal Title: Anticancer Res Volume: 35 Pages: 1251-1261
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Wilms' tumor gene WT1 promotes homologous recombination- mediated DNA damage repair (2015)
  • Author(s): Oji Y, Kobayashi J, et al.
  • Journal Title: Mol Carcinog Volume: in press Issue: 12 Pages: 1758-71
  • DOI: 10.1002/mc.22248
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a Novel C-Terminal Truncated WT1 Isoform with Antagonistic Effects against Major WT1 Isoforms. (2015)
  • Author(s): Tatsumi N, Hojo N, Sakamoto H, Inaba R, Moriguchi N, Matsuno K, Fukuda M, Matsumura A, Hayashi S, Morimoto S, Nakata J, Fujiki F, Nishida S, Nakajima H, Tsuboi A, Oka Y, Hosen N, Sugiyama H, Oji Y.
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0130578-e0130578
  • DOI: 10.1371/journal.pone.0130578
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An immunocompetent mouse model for MLL/AF9 leukemia reveals the potential of spontaneous cytotoxic T-cell response to an antigen expressed in leukemia cells (2015)
  • Author(s): Kana Hasegawa, Satomi Tanaka, Fumihiro Fujiki, Soyoko Morimoto, Hiroko Nakajima, Naoya Tatsumi, Jun Nakata, Satoshi Takashima, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Yusuke Oji, Atsushi Kumanogoh, Haruo Sugiyama, Naoki Hosen
  • Journal Title: PLoS ONE Volume: 10 Issue: 12 Pages: e0144594-e0144594
  • DOI: 10.1371/journal.pone.0144594
  • Peer Reviewed / Open Access
• [Journal Article] osen N, Sugiyama H, Oji Y. Deficiency in WT1-targeting microRNA-125a leads to myeloid malignancies and urogenital abnormalities. (2015)
  • Author(s): Tatsumi N, Hojo N, Yamada O, Ogawa M, Katsura Y, Kawata S, Morii E, Sakamoto H, Inaba R, Tsuda A, Fukuda I, Moriguchi N, Hasuwa H, Okabe M, Fujiki F, Nishida S, Nakajima H, Tsuboi A, Oka Y, Hosen N, Sugiyama H, Oji Y.
  • Journal Title: Oncogene Volume: 35 Issue: 8 Pages: 1003-14
  • DOI: 10.1038/onc.2015.154
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Deficiency in WT1-targeting microRNA-125a leads to myeloid malignancies and urogenital abnormalities. (2015)
  • Author(s): Tatsumi N, Hojo N, Yamada O, Ogawa M, Katsura Y, Kawata S, Morii E, Sakamoto H, Inaba R, Tsuda A, Fukuda I, Moriguchi N, Hasuwa H, Okabe M, Fujiki F, Nishida S, Nakajima H, Tsuboi A, Oka Y, Hosen N, Sugiyama H, Oji Y.
  • Journal Title: Oncogene Volume: in press
  • Peer Reviewed
• [Journal Article] Transduction of a Novel HLA-DRB1*04:05-restricted, WT1-specific TCR Gene into Human CD4+ T Cells Confers Killing Activity Against Human Leukemia Cells. (2015)
  • Author(s): Katsuhara A, Fujiki F, Aoyama N, Tanii S, Morimoto S, Oka Y, Tsuboi A, Nakajima H, Kondo K, Tatsumi N, Nakata J, Nakae Y, Takashima S, Nishida S, Hosen N, Sogo S, Oji Y, Sugiyama H.
  • Journal Title: Anticancer Res Volume: 35 Pages: 1251-1261
  • Peer Reviewed
• [Journal Article] The translation elongation factor eEF2 is a novel tumor-associated antigen overexpressed in various types of cancers. (2014)
  • Author(s): Oji Y, Tatsumni N, Izumoto S (34 名省略）
  • Journal Title: Int J Oncol Volume: 44 Issue: 5 Pages: 1461-1469
  • DOI: 10.3892/ijo.2014.2318
  • Peer Reviewed / Open Access
• [Journal Article] HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells. (2013)
  • Author(s): Lin Y, Fujiki F, Katsuhara A, Oka Y, Tsuboi A, Aoyama N, Tanii S, Nakajima H, Tatsumi N, Morimoto S, Tamanaka T, Tachino S, Hosen N, Nishida S, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: J Immunother. Volume: 36（3） Issue: 3 Pages: 159-70
  • DOI: 10.1097/cji.0b013e3182873581
  • Peer Reviewed
• [Journal Article] Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine (2013)
  • Author(s): Maeda T, Hosen N, Fukushima K, Tsuboi A, Morimoto S, Matsui T, Sata H, Fujita J, Hasegawa K, Nishida S, Nakata J, Nakae Y, Takashima S, Nakajima H, Fujiki F, Tatsumi N, Kondo T, Hino M, Oji Y, Oka Y, Kanakura Y, Kumanogoh A, Sugiyama H
  • Journal Title: Blood Cancer J Volume: 3 Issue: 8 Pages: e130-e130
  • DOI: 10.1038/bcj.2013.29
  • Peer Reviewed
• [Journal Article] In vivo eradication of MLL/ENL leukemia cells by NK cells in the absence of adaptive immunity. (2013)
  • Author(s): Nakata J, Nakano K, Okumura A, Mizutani Y, Kinoshita H, Iwai M, Hasegawa K, Morimoto S, Fujiki F, Tatsumi N, Nakajima H, Nakae Y, Nishida S, Tsuboi A, Oji Y, Oka Y, Sugiyama H, Kumanogoh A, Hosen N.
  • Journal Title: Leukemia. Volume: - Issue: 6 Pages: 1316-1325
  • DOI: 10.1038/leu.2013.374
  • Peer Reviewed
• [Journal Article] Comparison of Gwet’s AC1 with Fleiss’s kappa as an index for inter-examiner reliability of diagnosis in immunohistochemical evaluation of WT1 expression in tumors. (2013)
  • Author(s): Hori M, Oji Y, Utada M, Kato T, Anguille S, Wagner N, Duregon E, Hiraoka N, Udaka K, Izumoto S, Ohno S, Iwafuchi M, Ohashi H, Lammens M, Waelput W, O'Reilly R, Lundin E, Cilloni D, Letsch A, Fukuda M, Tatsumi N, Oka Y, Morii E, Pauwels P, Heike Y, Papotti M, Saglio G, Keilholz U, Berneman ZN, Sugiyama H, Ohno Y.
  • Journal Title: Japanese J of Applied IT Healthcare Volume: -
  • Peer Reviewed
• [Presentation] WT1を標的とするmiR-125a の骨髄増殖性腫瘍発症における役割 (2015)
  • Author(s): 辰巳直也、北條望、森井英一、蓮輪英毅、岡部勝、保仙直毅、尾路祐介、杉山治夫
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2015-10-08
• [Presentation] miR-125a 新規標的遺伝子Zbtb7aの同定とその機能解析 (2015)
  • Author(s): 北條望、辰巳直也、森口奈保子、松村晃秀、林清二、尾路祐介、杉山治夫
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県）
  • Year and Date: 2015-10-08
• [Presentation] eEF2特異的抗腫瘍CTL免疫応答のin vivoでの誘導 (2014)
  • Author(s): 中島博子、尾路祐介、村上由依、森井英一、赤尾聡紀、小田嶋聡子、辰巳直也、福田茉莉、待谷貴央、岩井美樹、北條望、岡芳弘、杉山治夫
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] eEF2の癌遺伝子様機能とeEF2特異的免疫応答の誘導
  • Author(s): 尾路祐介、辰巳直也、福田茉莉、中塚新一、藤木文博、中島博子、長谷川加奈、根津理一郎、森井英一、坪井昭博、岡芳弘、杉山治夫
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜