Elucidation of colorectal cancer pathology by interaction between nuclear pore protein and chromatin

• Project/Area Number: 17K08655
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: Wong Richard 金沢大学, ナノ生命科学研究所, 教授 (30464035)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 核膜孔 / クロマチン / 核膜孔複合体 / 大腸がん

Outline of Final Research Achievements

The cell nucleus is covered with a double membrane called the nuclear envelope. Nuclear pores, which are the only gates in the nuclear envelope, are used for active transfer of substances inside and outside the nucleus such as proteins and mRNA. The nuclear pore is composed of a nuclear pore complex (Nuclear Pore Complex: NPC), and the complex is composed of about 30 different NPC proteins (nucleoporins). In this research project, we aimed to explore the pathological mechanism of the relationship of NPC and chromatin in the progression of colorectal cancer. During the implementation period, we clarified the role of nucleoporins in cancer pathology.

Academic Significance and Societal Importance of the Research Achievements

大腸がんは日本において死亡率第二位のがんであり、早期診断法や新規治療法の開発が早急に必要ながんの一つである。これら新規診断・治療法の開発を行うためには、大腸がん発生・進展メカニズムを知ることが重要である。この研究の成果は、がん細胞における遺伝子ゲーティングと遺伝子発現における核膜孔タンパク質の役割の理解への大きな飛躍をもたらし、得られた知見は核を標的としたナノドラッグデリバリーシステムといった治療法への応用が期待される。

Research Products

• [Journal Article] Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines (2020)
  • Author(s): Hazawa M, Yoshino H, Nakagawa Y, Shimizume R, Nitta K, Sato Y, Sato M, Wong RW, Kashiwakura I
  • Journal Title: Cancers Volume: 12(4) Issue: 4 Pages: 908-908
  • DOI: 10.3390/cancers12040908
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells. (2020)
  • Author(s): Lim KS, Yong ZWE, Wang H, Tan TZ, Huang RY, Yamamoto D, Inaki N, Hazawa M, Wong RW, Oshima H, Oshima M, Ito Y, Voon DC.
  • Journal Title: J Biol. Chem. Volume: 未定 Issue: 19 Pages: 6387-6400
  • DOI: 10.1074/jbc.ra120.012943
  • Peer Reviewed / Open Access
• [Journal Article] Nucleoporin TPR (translocated promoter region, nulear basket protein) upregulation alters MTOR-HSF1 trails and suppresses autophagy induction in ependymoma. (2020)
  • Author(s): Dewi FRP, Jiapear S, Kobayashi A, Hazawa M, Ikliptikawati DK, Hartono, Sabit H, Nakada M, Wong RW
  • Journal Title: Autophagy Volume: 24 Issue: 4 Pages: 1-12
  • DOI: 10.1080/15548627.2020.1741318
  • Peer Reviewed / Open Access
• [Journal Article] Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma (2019)
  • Author(s): Hazawa Masaharu、Sakai Kie、Kobayashi Akiko、Yoshino Hironori、Iga Yoshihiro、Iwashima Yuki、Lim Kee Sing、Chih-Cheng Voon Dominic、Jiang Yan-Yi、Horike Shin-ichi、Lin De-Chen、Wong Richard W.
  • Journal Title: Oncogene Volume: 39 Issue: 10 Pages: 2212-2223
  • DOI: 10.1038/s41388-019-1137-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nucleoporin Nup58 Localizes to centrosomes and mid-bodies during mitosis. (2019)
  • Author(s): Hartono, Hazawa M, Lim KS, Dewi FRP, Kobayashi A, Wong RW
  • Journal Title: Cell Division Volume: 14 Issue: 1
  • DOI: 10.1186/s13008-019-0050-z
  • Peer Reviewed / Open Access
• [Journal Article] Direct Visualization of Avian Influenza H5N1 Hemagglutinin Precursor and its Conformational Change by High-Speed Atomic Force Microscopy (2019)
  • Author(s): Lim SK, Mohamed MS, Wang H, Hartono, Hazawa M, Kobayashi A, Voon DC, Kodera N, Ando T and Wong RW
  • Journal Title: BBA - General Subjects Volume: 印刷中 Issue: 2 Pages: 129313-129313
  • DOI: 10.1016/j.bbagen.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] Targeting nucleoporin POM121-importin β axis in prostate cancer. (2018)
  • Author(s): Lim SK and Wong RW
  • Journal Title: Cell Chem. Biol. Volume: 25(9) Issue: 9 Pages: 1056-1058
  • DOI: 10.1016/j.chembiol.2018.09.003
  • Peer Reviewed / Open Access
• [Journal Article] Colorectal cancer cells require glycogen synthase kinase-3β for sustaining mitosis via translocated promoter region (TPR)-dynein interaction (2018)
  • Author(s): Dewi FRP, Domoto T, Hazawa M, Kobayashi A, Douwaki T, Minamoto T and Wong RW
  • Journal Title: Oncotarget Volume: 9(17) Pages: 13337-13352
  • Peer Reviewed / Open Access
• [Journal Article] Rock-dependent phosphorylation of NUP62 regulates p63 nuclear transport and cell fate of squamous cell carcinoma. (2018)
  • Author(s): Hazawa M, Lin D, Kobayashi A, Jiang YY, Dewi FRP, Mohamed MS, Hartono H, Nakada S, Meguro-Horike M, Horike S, Koeffler H and Wong RW
  • Journal Title: EMBO Rep. Volume: 19 Issue: 1 Pages: 73-88
  • DOI: 10.15252/embr.201744523
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-Speed Atomic Force Microscopy Reveals Loss of Nuclear Pore Resilience as a Dying Code in Colorectal Cancer Cells. (2017)
  • Author(s): Mohamed MS, Kobayashi A, Taoka A, Watanabe-Nakayama T, Kikuchi Y, Hazawa M, Minamoto T, Fukumori Y, Kodera N, Uchihashi T, Ando T, Wong RW
  • Journal Title: ACS Nano. Volume: 11(6) Issue: 6 Pages: 5567-5578
  • DOI: 10.1021/acsnano.7b00906
  • Peer Reviewed / Open Access
• [Journal Article] ZNF750 is a lineage-specific tumor suppressor in squamous cell carcinoma. (2017)
  • Author(s): Hazawa M, Lin D, Handral H, Xu L, Chen Y, Jiang YY, Thippeswamy A, Ding LW, Meng X, Sharma A, Samuel S, Movahednia M, Wong RW, Yang H, Tong C, and Koeffler H
  • Journal Title: Oncogene Volume: 36(16) Issue: 16 Pages: 2243-2254
  • DOI: 10.1038/onc.2016.377
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] NUP88 は Nbs1 の核内局在を調節し、相同組み換え修復を活性化する。 (2019)
  • Author(s): 伊賀祥紘、岩嶋由紀、小林亜紀子、安田武嗣、源利成、羽澤勝治、Richard Wong
  • Organizer: 令和元年度若手放射線生物学研究会専門研究会
• [Presentation] 病態特異的Karyopherinの発現異常はOncogenicシグナル伝達を確立する (2019)
  • Author(s): 羽澤 勝治、ウォング リチャード
  • Organizer: 第78回癌学会学術総会
• [Presentation] 核膜孔複合体によるゲノム配置規制を介した転写活性機構 (2019)
  • Author(s): 羽澤勝治、岩嶋由紀、小林亜紀子、Richard Wong
  • Organizer: 第25回DNA複製・組換え・修復ワークショップ
• [Presentation] The nuclear pore complex: nanomachine as gatekeeper of molecular transport across nuclear membranes. (2018)
  • Author(s): Richard Wong
  • Organizer: The 2nd NanoLSI International Symposium - Towards Establishment of New Research Field: Nanoprobe Life Science
  • Int'l Joint Research / Invited
• [Presentation] High-speed atomic force microscopy visualization of the spatiotemporal dynamics of the nuclear nanomachine- the nuclear pore complex (2018)
  • Author(s): Richard Wong
  • Organizer: 第18回日本蛋白質科学会年会(ワークショップ)
  • Invited
• [Presentation] Molecular imaging of spatiotemporal structural dynamics of the Nuclear Pore Complex (2018)
  • Author(s): Richard Wong
  • Organizer: 新学術領域研究「動的構造生命」班会議
  • Invited
• [Presentation] Nuclear Pore Complex (2018)
  • Author(s): Richard Wong
  • Organizer: Research Center for Advance Science & Technology Seminar, The University of Tokyo
  • Invited
• [Presentation] Disease-specific alteration of karyopherin-alpha subtypes establishes feedforward oncogenic signaling in squamous cell carcinoma. (2018)
  • Author(s): Hazawa M, Sakai K, Kobayashi A, Wong RW.
  • Organizer: THE 2018 ASCB | EMBO MEETING
  • Int'l Joint Research
• [Presentation] Nuclear transport system caused by disease-specific Karyopherin alternation (2018)
  • Author(s): Sakai K, Hazawa M, Kobayashi A, Wong RW.
  • Organizer: Joint Annual Meeting of 70th JSCB and 51st JSDB
• [Presentation] Visualization spatiotemporal dynamics of RNA export factor RAE1 and RNAs complex by nanoscopic imaging. (2018)
  • Author(s): Kobayashi A, Kodera N, Morikawa K, Wong RW.
  • Organizer: The 1st WPI NanoLSI site visit
  • Int'l Joint Research
• [Presentation] The role of nucleoporin NUP58 during division (2018)
  • Author(s): Hartono H, Hazawa M, Dewi F, Kobayashi A, Mohamed MS, Wong RW.
  • Organizer: Joint Annual Meeting of 70th JSCB and 51st JSDB
• [Presentation] An oncogenic role of Tpr in Ependymoma (2018)
  • Author(s): Dewi F, Jiapaer S, Hazawa M, Sabit H, Kobayashi A, Hartono H, Nakada M, Wong RW
  • Organizer: Joint Annual Meeting of 70th JSCB and 51st JSDB
• [Presentation] 上衣腫におけるヌクレオポリン構成分子Tprはオートファジー誘導細胞死抑制因子である (2018)
  • Author(s): 淑瑠ヘムラサビット、Jiapaer S, 玉井翔、Dewi F, 羽澤勝治、小林亜紀子、Wong RW, 中田光俊
  • Organizer: 第35回日本脳腫瘍病理学会
• [Presentation] 高速原子間力顕微鏡(HS-AFM)によるRNA輸送因子(RAE1)とRNAの動態観察 (2018)
  • Author(s): 森川亮志、古寺哲幸、小林亜紀子、Richard W. Wong
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Cisplatin-Induced Plasmid DNA Conformations Revealed by High-Speed Atomic Force Microscopy (2018)
  • Author(s): Hanbo Wang, Mahmoud Shaaban Mohamed, Kee Siang Lim, Hiroki Konnno, Takahiro Nakayama, Noriyuki Kodera, Richard W. Wong
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] DNA損傷応答における核膜孔複合体の役割 (2018)
  • Author(s): 伊賀 祥紘、羽澤 勝治、Richard W. Wong
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] THE SPATIOTEMPORAL DYNAMICS OF NUCLEOPORIN NUP58 DURING CELL DIVISION (2018)
  • Author(s): Hartono Hartono, Masaharu Hazawa, Firli Rahmah Primula Dewi, Akiko Kobayashi, Mahmoud Shaaban Mohamed, Lim Kee Siang, Richard W. Wong
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Spatiotemporal dynamics of the nuclear nanomachine-the nuclear pore complex. (2018)
  • Author(s): Richard Wong
  • Organizer: The 1st NanoLSI International Symposium - Towards Establishment of New Research Field: Nanoprobe Life Science
  • Int'l Joint Research / Invited
• [Presentation] Identifying nanoscopic spider cobweb features of native nuclear pores in cancer cells. (2018)
  • Author(s): Richard Wong
  • Organizer: International Symposium on Atomic Force Microscopy at Solid-Liquid Interfaces
  • Int'l Joint Research / Invited
• [Presentation] Molecular imaging of protein structure and traffic dynamics between cytoplasm and nucleus. (2018)
  • Author(s): Richard Wong
  • Organizer: The 3rd WPI NanoLSI Transdisciplinary Research Promotion Seminar
  • Invited
• [Presentation] Nuclear pore architecture and dynamics. (2018)
  • Author(s): Richard Wong
  • Organizer: 京都大学大学院工学研究科分子工学専攻生体分子機能化学セミナー
  • Invited
• [Presentation] 動的核膜孔複合体の構造と機能と病態 (2017)
  • Author(s): Richard Wong
  • Organizer: 金沢大学・北陸先端科学技術大学院大学融合科学共同専攻第２回共同ワークショップ
  • Invited
• [Presentation] Structure, dynamics and function of nuclear pore complexes (2017)
  • Author(s): Richard Wong
  • Organizer: 革新的統合バイオ研究コア ワークショップ-多様な生命現象数理モデル研究
  • Invited
• [Presentation] High-speed atomic force microscopy visualization of the nuclear pores dynamics in colon cancer cells (2017)
  • Author(s): Richard Wong
  • Organizer: 第17回日本蛋白質科学会年会
• [Presentation] 核膜孔複合体蛋白群の動的構造と機能と病態 (2017)
  • Author(s): Richard Wong
  • Organizer: 金沢大学・北陸先端科学技術大学院大学融合科学共同専攻第1回共同ワークショップ
  • Invited
• [Presentation] ROCK-dependent phosphorylation of NUP62 regulates p63 nuclear transport in squamous cell carcinoma (2017)
  • Author(s): Hazawa M, Kobayashi A, Wong RW
  • Organizer: The 2017 ASCB | EMBO Meeting
  • Int'l Joint Research
• [Presentation] Nuclear Pore Selective Barrier Dynamics as Revealed by HigSpeed Atomic Force Microscopy in Colorectal Cancer Cells (2017)
  • Author(s): Mohamed MS, Kikuchi Y, Watanabe-Nakayama T, Taoka A, Kobayashi A, Hazawa M, Kodera N, Uchihashi T, Minamoto T, Fukumori Y, Ando T, Wong RW
  • Organizer: The 2017 ASCB | EMBO Meeting
  • Int'l Joint Research
• [Presentation] Colorectal cancer cells require glycogen synthase kinase3 for sustaining mitosis via translocated promotor region (Tpr)‐dynein interaction. (2017)
  • Author(s): Dewi F, Domoto T, Hazawa M, Kobayashi A, Douwaki T, Minamoto T, Wong RW
  • Organizer: The 2017 ASCB | EMBO Meeting
  • Int'l Joint Research
• [Presentation] Nuclear Pore Complex Dynamics Revealed by High-Speed Atomic Force Microscopy in Colorectal Cancer Cells. (2017)
  • Author(s): Mohamed MS, Kikuchi Y, Watanabe-Nakayama T, Taoka A, Kobayashi A, Hazawa M, Kodera N, Uchihashi T, Minamoto T, Fukumori Y, Ando T, Wong RW
  • Organizer: International Symposium on Atomic Force Microscopy at Solid-Liquid Interfaces
  • Int'l Joint Research
• [Presentation] Loss of Nuclear Pore Selective Barrier Revealed by High-Speed Atomic Force Microscopy in Colorectal Cancer Cells (2017)
  • Author(s): Mohamed MS, Kikuchi Y, Watanabe-Nakayama T, Taoka A, Kobayashi A, Hazawa M, Kodera N, Uchihashi T, Minamoto T, Fukumori Y, Ando T, Wong RW
  • Organizer: 日本生物物理学会第55回年会
• [Presentation] High-speed atomic force microscopy visualization of the nuclear pores dynamics in colon cancer cells (2017)
  • Author(s): Mohamed MS, Kikuchi Y, Watanabe-Nakayama T, Taoka A, Kobayashi A, Hazawa M, Kodera N, Uchihashi T, Minamoto T, Fukumori Y, Ando T, Wong RW
  • Organizer: 第17回日本蛋白質科学会年会
• [Presentation] 皮膚組織幹細胞におけるNup153 の役割 (2017)
  • Author(s): 塚原涼太，小林亜紀子，Wong RW，羽澤勝治
  • Organizer: 第69回細胞生物学会大会
• [Presentation] Mitotic crosstalks between translocated promoter region (Tpr) and Aurora A are key determinants of Ependymoma. (2017)
  • Author(s): Dewi F, Kobayashi A, Sabit H, Douwaki T, Dong Y, Hazawa M, Hartono, Shabierjiang J, Nakada M, Wong RW
  • Organizer: 第69回細胞生物学会大会
• [Presentation] Dynamics and Behavior of Cancer Nuclear Pore Complexes as Revealed by High-Speed Atomic Force Microscopy (2017)
  • Author(s): Mohamed MS, Kikuchi Y, Watanabe-Nakayama T, Taoka A, Kobayashi A, Hazawa M, Kodera N, Uchihashi T, Minamoto T, Fukumori Y, Ando T, Wong RW
  • Organizer: 日本生化学会北陸支部第35回大会
• [Presentation] Colorectal cancer cells require glycogen synthase kinase-3β for Sustaining mitosis via translocated promoter region(Tpr)-dynein interaction (2017)
  • Author(s): Dewi F, Domoto T, Hazawa M, Kobayashi A, Douwaki T, Minamoto T, Wong RW
  • Organizer: 日本生化学会北陸支部第35回大会
• [Book] Nuclear Pore Complexes in Genome Organization, Function and Maintenance (2018)
  • Author(s): Herausgegeben von D'Angelo, Maximiliano ( References10: Richard Wong)
  • Publisher: Springer International Publishing
  • ISBN: 9783319716121
• [Remarks] 分子ナノゲート核膜孔複合体分子が細胞の運命を決定する仕組みを解明
  • URL: https://nanolsi.kanazawa-u.ac.jp/achievements/achievements-955/
• [Remarks] 世界最速の原子間力顕微鏡を用いて大腸がん細胞核核膜孔の動きの撮影に世界で初めて成功！
  • URL: https://www.kanazawa-u.ac.jp/rd/47455
• [Patent(Industrial Property Rights)] 「高速原子間力顕微鏡による細胞小器官の観察のための試料調製方法」 (2017)
  • Inventor(s): ウォングウィンチェンリチャード 他
  • Industrial Property Rights Holder: ウォングウィンチェンリチャード 他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-223106
  • Filing Date: 2017