Development of a miRNA delivery system using Ago2/miRNA complexes modified with cancer specific peptide.

• Project/Area Number: 26461961
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Tokyo Medical University
• Principal Investigator: Ueda Shinobu 東京医科大学, 医学部, 助手 (00521874)
• Co-Investigator(Kenkyū-buntansha): 須藤 カツ子 東京医科大学, 医学部, 兼任講師 (50126091) ; 黒田 雅彦 東京医科大学, 医学部, 主任教授 (80251304) ; 高梨 正勝 東京医科大学, 医学部, 講師 (80312007)
• Co-Investigator(Renkei-kenkyūsha): TSUTCHIDA Akihiko 東京医科大学, 医学部, 主任教授 (50207396)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 乳がん / miRNA / ジーンデリバリー / Ago2 / 遺伝子治療

Outline of Final Research Achievements

It is known that dysregulation of microRNAs (miRNAs) contributes to the development and progression of cancers. The circulating miRNAs in the bloodstream escape from attacking of blood RNase activity by encapsulation in membrane-bound vesicles such as exosomes. However, Arroyo et al. reported that a significant portion of circulating miRNA is associated with Argonaute2 (Ago2), the effector component of the miRNA-induced silencing complex that directly binds to miRNAs and mediates messenger RNA repression in cells. In this study, we examined whether Ago2/miRNA complexes were new useful tools for gene delivery. The extracellular Ago2 complexes were in small amount of components in culture medium of breast cancer cells (MCF-7). The cell growth of MCF-7 cells was inhibited by using culture medium in miR-27a/Ago2 overexpressed HEK293 cells. Our study suggests that Ago2/miRNA complexes may be useful an effective miRNA delivery system for cancer therapy.

Research Products

• [Journal Article] Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis. (2017)
  • Author(s): Yamada Y, Takanashi M, Sudo K, Ueda S, Ohno SI, Kuroda M.
  • Journal Title: PLoS One. Volume: 12 Issue: 2 Pages: 0171957-0171957
  • DOI: 10.1371/journal.pone.0171957
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRG4 expression in myxoid liposarcoma maintains tumor cell growth through suppression of an antitumor cytokine IL-24. (2017)
  • Author(s): Oikawa K, Mizusaki A, Takanashi M, Ozaki T, Sato F, Kuroda M, Muragaki Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 25;485(1) Issue: 1 Pages: 209-214
  • DOI: 10.1016/j.bbrc.2017.02.055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An improved Red/ET recombineering system and mouse ES cells culture conditions for the generation of targeted mutant mice (2017)
  • Author(s): Kumagai K, Takanashi M, Ohno SI, Kuroda M, Sudo K.
  • Journal Title: Experimental Animals Volume: 66 Issue: 2 Pages: 125-136
  • DOI: 10.1538/expanim.16-0075
  • NAID: 130005635561
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. (2017)
  • Author(s): Michio Nakaya,Kenji Watari,Mitsuru Tajima,Takeo Nakaya,Shoichi Matsuda,Hiroki Ohara,Hiroaki Nishihara,Hiroshi Yamaguchi,Akiko Hashimoto,Mitsuho Nishida,Akiomi Nagasaka,Yuma Horii,Hiroki Ono,Gentaro Iribe,Ryuji Inoue,Makoto Tsuda,Kazuhide Inoue,Akira Tanaka,Masahiko Kuroda,Shigekazu Nagata,Hitoshi Kurose
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 1 Pages: 383-401
  • DOI: 10.1172/jci83822
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of novel small hairpin RNAs that do not require processing by dicer or AGO2 (2016)
  • Author(s): Ohno S, Itano K, Harada Y, Asada K, Oikawa K, Kashiwazako M, Okuyama H, Kumagai K, Takanashi M, Sudo K, Ikeda N, Kuroda M.
  • Journal Title: Mol Ther Volume: 24 Issue: 7 Pages: 1278-1289
  • DOI: 10.1038/mt.2016.81
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice. (2016)
  • Author(s): Matsumoto Y, Itami S, Kuroda M, Yoshizato K, Kawada N, Murakami Y.
  • Journal Title: Mol Ther. Volume: 24 Issue: 10 Pages: 1848-59
  • DOI: 10.1038/mt.2016.127
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HLA-G expression is regulated by miR-365 in trophoblasts under hypoxic conditions. (2016)
  • Author(s): Mori A, Nishi H, Sasaki T, Nagamitsu Y, Kawaguchi R, Okamoto A, Kuroda M, Isaka K.
  • Journal Title: Placenta. Volume: 45 Pages: 37-41
  • DOI: 10.1016/j.placenta.2016.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Solitary Pulmonary Capillary Hemangioma of Adult Cases: Clinicopathologic Characteristics as an Unrecognized Entity. (2016)
  • Author(s): Hashimoto H, Kurata A, Fujiwara M, Hara K, Matsumoto J, Kusakabe M, Tachibana K, Nashiro T, Terado Y, Akahane M, Usui K, Suzuki Y, Kondo H, Kamma H, Kuroda M, Horiuchi H.
  • Journal Title: Am J Surg Pathol. Volume: 40 Issue: 10 Pages: 1380-1389
  • DOI: 10.1097/pas.0000000000000708
  • Peer Reviewed / Open Access
• [Journal Article] Topical Use of Angiopoietin-like Protein 2 RNAi-loaded Lipid Nanoparticles Suppresses Corneal Neovascularization. (2016)
  • Author(s): Taketani Y, Usui T, Toyono T, Shima N, Yokoo S, Kimakura M, Yamagami S, Ohno S, Onodera R, Tahara K, Takeuchi H, Kuroda M.
  • Journal Title: Mol Ther Nucleic Acids. Volume: 5 Pages: e292-e292
  • DOI: 10.1038/mtna.2016.1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA and gynecologic cancers. (2016)
  • Author(s): Kanekura K, Nishi H, Isaka K, Kuroda M.
  • Journal Title: J Obstet Gynaecol Res. Volume: 10.1111/jog.12995 Issue: 6 Pages: 052-052
  • DOI: 10.1111/jog.12995
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel types of small RNA exhibit sequence- and target-dependent angiogenesis suppression without activation of Toll-like Receptor 3 in an age-related macular degeneration (AMD) mouse model. (2015)
  • Author(s): Takanashi M, Sudo K, Ueda S, Ohno S, Yamada Y, Osakabe Y, Goto H, Matsunaga Y, Ishikawa A, Usui , Kuroda M.
  • Journal Title: Mol Ther Nucleic Acids. Volume: 4 Pages: e258-e258
  • DOI: 10.1038/mtna.2015.34
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation. (2015)
  • Author(s): Yoon JH, Sudo K, Kuroda M, Kato M, Lee IK, Han JS, Nakae S, Imamura T, Kim J, Ju JH, Kim DK, Matsuzaki K, Weinstein M, Matsumoto I, Sumida T, Mamura M
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 7600-7600
  • DOI: 10.1038/ncomms8600
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers. (2015)
  • Author(s): Morita H, Arae K, Unno H, Miyauchi K, Toyama S, Nambu A, Oboki K, Ohno T, Motomura K, Matsuda A, Yamaguchi S, Narushima S, Kajiwara N, Iikura M, Suto H, McKenzie AN, Takahashi T, Karasuyama H, Okumura K, Azuma M, Moro K, Akdis CA, Galli SJ, Koyasu S, Kubo M, Sudo K, Saito H, Matsumoto K, Nakae S.
  • Journal Title: Immunity Volume: 43 Issue: 1 Pages: 175-86
  • DOI: 10.1016/j.immuni.2015.06.021
  • NAID: 40020962854
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] IL-1 Receptor Type 2 Suppresses Collagen-Induced Arthritis by Inhibiting IL-1 Signal on Macrophages. (2015)
  • Author(s): Shimizu K, Nakajima A, Sudo K, Liu Y, Mizoroki A, Ikarashi T, Horai R, Kakuta S, Watanabe T, Iwakura Y.
  • Journal Title: J Immunol. Volume: 194(7) Issue: 7 Pages: 3156-3168
  • DOI: 10.4049/jimmunol.1402155
  • Peer Reviewed / Open Access
• [Journal Article] The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1β. (2015)
  • Author(s): Fujita H, Yagishita N, Aratani S, Saito-Fujita T, Morota S, Yamano Y, Hansson MJ, Inazu M, Kokuba H, Sudo K, Sato E, Kawahara K, Nakajima F, Hasegawa D, Higuchi I, Sato T, Araya N, Usui C, Nishioka K, Nakatani Y, Maruyama I, Usui M, Hara N, Uchino H, Elmer E, Nishioka K, Nakajima T.
  • Journal Title: EMBO J. Volume: 34 Issue: 8 Pages: 1042-55
  • DOI: 10.15252/embj.201489897
  • Peer Reviewed / Open Access
• [Journal Article] CCR8 regulates contact hypersensitivity by restricting cutaneous dendritic cell migration to the draining lymph nodes. (2015)
  • Author(s): Yabe R, Shimizu K, Shimizu S, Azechi S, Choi BI, Sudo K, Kubo S, Nakae S, Ishigame H, Kakuta S, Iwakura Y.
  • Journal Title: Int Immunol. Volume: 27(4) Issue: 4 Pages: 169-181
  • DOI: 10.1093/intimm/dxu098
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like 7 is an anti-angiogenic protein required to prevent vascularization of the cornea. (2015)
  • Author(s): Toyono T, Usui T, Yokoo S, Taketani Y, Nakagawa S, Kuroda M, Yamagami S, Amano S.
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: e0116838-e0116838
  • DOI: 10.1371/journal.pone.0116838
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of the Human Papillomavirus mRNA Test for the detection of cervical lesions in Japan. (2015)
  • Author(s): Nakayama Y, Yamada M, Kurata A, Kiseki H, Kuroda M.
  • Journal Title: Eur J Gynaec Oncol (European journal of gynaecological oncology). Volume: in press
  • Peer Reviewed
• [Journal Article] Immaturity of smooth muscle cells in the neointima is associated with acute coronary syndrome. (2015)
  • Author(s): Horita A, Kurata A, Ohno S, Shimoyamada H, Saito I, Kamma H, Kuroda M.
  • Journal Title: Cardiovasc Pathol Volume: 24 Issue: 1 Pages: 26-32
  • DOI: 10.1016/j.carpath.2014.09.003
  • Peer Reviewed / Open Access
• [Journal Article] Unique expression pattern of viral proteins in human herpesvirus 8-positive plasmablastic lymphoma: a case report. (2014)
  • Author(s): Yamada M, Katano H, Yotsumoto M, Hashimoto H, Muramatsu T, Shiotsuka M, Fukutake K, Kuroda M.
  • Journal Title: Int J Clin Exp Pathol. Volume: 15;7(9) Pages: 6415-6418
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Multifocal Kaposiform Hemangioendothelioma in Multiple Visceral Organs: An Autopsy of 9-Day-Old Female Baby. (2014)
  • Author(s): Takeo Nakaya, Kiyoko Morita, Atsushi Kurata,Tetsuo Ushiku, Takashi Igarashi, Masahiko Kuroda, Masashi Fukayama.
  • Journal Title: Human Pathology. Volume: 45 Issue: 8 Pages: 1773-1777
  • DOI: 10.1016/j.humpath.2014.03.019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 乳がん幹細胞の酸化ストレス抵抗性におけるmiR-27aの作用 (2016)
  • Author(s): 上田しのぶ, 髙梨正勝, 黒田雅彦
  • Organizer: 第１０５回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12
• [Presentation] 肺線維症に対するmiR-29b補充療法 (2015)
  • Author(s): 山田佑子、髙梨正勝、須藤カツ子、上田しのぶ、黒田雅彦
  • Organizer: 第１０４回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-04-30
• [Presentation] The development of short form of mimic microRNA for lung cancer therapy (2014)
  • Author(s): Shin-ichiro Ohno, karen Itano, Yuichirou Harada, Masakatsu Takanashi, Katsuko Sudo, Norihiko Ikeda, Masahiko Kuroda
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Analysis of a novel molecular pathway induced by TLS-CHOP for myxoid liposarcoma tumorigenesis and tumor progression (2014)
  • Author(s): Kosuke Oikawa, Masakatsu Takanashi, Masako Nakanishi, Fuyuki Sato, Masahiko Kuroda, Yasuteru Muragaki
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] 自己細胞由来のエクソソームによるドラッグデリバリーシステムへの応用 (2014)
  • Author(s): 高梨正勝、上田しのぶ、須藤カツ子、石川章夫、黒田雅彦
  • Organizer: 第１０３回日本病理学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 肺がんを効果的に抑制するMimic microRNAの新規形状の探索 (2014)
  • Author(s): 大野慎一郎、板野華連、原田裕一郎、高梨正勝、須藤カツ子、黒田雅彦
  • Organizer: 第１０３回日本病理学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 胃がん細胞株における上皮間葉移行に関与するマイクロRNA200cとその標的の検出 (2014)
  • Author(s): 倉田厚、山田正俊、橋本浩次、藤田浩司、大野慎一郎、高梨正勝、黒田雅彦
  • Organizer: 第１０３回日本病理学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 胃癌組織におけるPD-L1の発現検討 (2014)
  • Author(s): 山田正俊、藤田浩司、倉田厚、黒田雅彦
  • Organizer: 第１０３回日本病理学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-04-24
• [Book] グリオーマ治療のDecision Making 脳神経外科診療プラクティス (2016)
  • Author(s): 上田しのぶ 黒田雅彦
  • Total Pages: 314
  • Publisher: 文光堂
• [Book] 病理と臨床 (2014)
  • Author(s): 上田しのぶ、高梨正勝、黒田雅彦
  • Total Pages: 8
  • Publisher: 文光堂
• [Remarks] 東京医科大学 分子病理学分野
  • URL: http://www.tokyo-med.ac.jp/molpathol/
• [Remarks] 東京医科大学・分子病理学分野
  • URL: http://www.tokyo-med.ac.jp/molpathol/