An enhancement in the sensitivity of refractory pancreatic cancer cells to anti-tumor drugs through the functional regulation of RUNX2.

• Project/Area Number: 15K08412
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: OZAKI TOSHINORI 千葉県がんセンター(研究所), 発がん研究グループ DNA損傷シグナル研究室, 室長 (40260252)
• Co-Investigator(Kenkyū-buntansha): 永瀬 浩喜 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究所長 (90322073)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: RUNX2 / 膵臓がん / 抗がん剤感受性 / 膵がん / 薬剤耐性 / TAp63 / TAp73 / p53 / ゲムシタビン

Outline of Final Research Achievements

RUNX2 which belongs to RUNX transcription factor family, plays a vital role in the regulation of osteogenesis. Recently, accumulating evidence demonstrated that RUNX2 is expressed at higher level in numerous human cancer tissues compared to their corresponding normal ones, indicating that RUNX2 might have a pro-oncogenic role. In this study, we have asked whether RUNX2 silencing could enhance gemcitabine (GEM) sensitivity of pancreatic cancer cells.
siRNA-mediated knockdown of RUNX2 increased GEM sensitivity of p53-null AsPC-1, p53-mutated MiaPaCa-2 and p53-mutated Panc-1 cells. Intriguingly, RUNX2 depletion caused a marked induction and activation of TAp73 and TAp63 in AsPC-1 cells and MiaPaCa-2/Panc-1 cells, respectively. Similar results were also obtained in spheres generated from MiaPaCa-2 cells. Thus, our present observations suggest that RUNX2 depletion improves GEM sensitivity of pancreatic cancer cells through the potentiation of TAp73/TAp63-dependent cell death pathway.

Research Products

• [Journal Article] Hydrophobic structure of hairpin ten-ring pyrrole-imidazole polyamides enhances tumor tissue accumulation/retention in vivo (2018)
  • Author(s): Inoue Takahiro、Shimozato Osamu、Matsuo Nina、Mori Yusuke、Shinozaki Yoshinao、Lin Jason、Watanabe Takayoshi、Takatori Atsushi、Koshikawa Nobuko、Ozaki Toshinori、Nagase Hiroki
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 9 Pages: 2337-2344
  • DOI: 10.1016/j.bmc.2018.03.029
  • Peer Reviewed
• [Journal Article] Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53 mutated pancreatic cancer MiaPaCa 2 spheres. (2018)
  • Author(s): Sang M, Nakamura M, Ogata T, Sun D, Shimozato O, Nikaido T, Ozaki T.
  • Journal Title: Oncol Rep. Volume: 印刷中 Pages: 2749-2758
  • DOI: 10.3892/or.2018.6344
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea. (2018)
  • Author(s): Matsumura T, Terada J, Kinoshita T, Sakurai Y, Yahaba M, Tsushima K, Sakao S, Nagashima K, Ozaki T, Kobayashi Y, Hiwasa T, Tatsumi K.
  • Journal Title: PLOS One Volume: 13 Issue: 3 Pages: 1-1
  • DOI: 10.1371/journal.pone.0195015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of RUNX2 on drug-resistant human pancreatic cancer cells with p53 mutations. (2018)
  • Author(s): Ozaki T, Yu M, Yin D, Sun D, Zhu Y, Bu Y, Sang M.
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 309-309
  • DOI: 10.1186/s12885-018-4217-9
  • Peer Reviewed / Open Access
• [Journal Article] Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells. (2017)
  • Author(s): Morita K, Noura M, Tokushige C, Maeda S, Kiyose H, Kashiwazaki G, Taniguchi J, Bando T, Yoshida K, Ozaki T, Matsuo H, Ogawa S, Liu PP, Nakahata T, Sugiyama H, Adachi S, Kamikubo Y.
  • Journal Title: Sci Rep. Volume: 7(1) Issue: 1 Pages: 16604-16604
  • DOI: 10.1038/s41598-017-16799-z
  • NAID: 120006368172
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depletion of runt-related transcription factor 2 (RUNX2) enhances SAHA sensitivity of p53-mutated pancreatic cancer cells through the regulation of mutant p53 and TAp63. (2017)
  • Author(s): Ogata T, Nakamura M, Sang M, Yoda H, Hiraoka K, Yin D, Sang M, Shimozato O, Ozaki T.
  • Journal Title: PLoS One Volume: 12 Issue: 7 Pages: e0179884-e0179884
  • DOI: 10.1371/journal.pone.0179884
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells. (2017)
  • Author(s): Hoshi R, Watanabe Y, Ishizuka Y, Hirano T, Nagasaki-Maeoka E, Yoshizawa S, Uekusa S, Kawashima H, Ohashi K, Sugito K, Fukuda N, Nagase H, Soma M, Ozaki T, Koshinaga T and Fujiwara K.
  • Journal Title: ONCOLOGY REPORTS Volume: 37 Issue: 4 Pages: 2459-2464
  • DOI: 10.3892/or.2017.5477
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Improvement of gemcitabine sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 cells by RUNX2 depletion-mediated augmentation of TAp73-dependent cell death. (2016)
  • Author(s): Nakamura M, Sugimoto H, Ogata T, Hiraoka K, Yoda H, Sang M, Sang M, Zhu Y, Yu M, Shimozato O, Ozaki T.
  • Journal Title: Oncogenesis Volume: 5 Issue: 6 Pages: e233-e233
  • DOI: 10.1038/oncsis.2016.40
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High mutation levels are compatible with normal embryonic development in Mlh1-deficient mice. (2016)
  • Author(s): Fan X, Li Y, Zhang C, Sang M, Cai J, Li Q, Ozaki T, Ono T, He D.
  • Journal Title: Radiat. Res. Volume: 186 Pages: 377-384
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptional regulation of BMCC1 mediated by E2F1 in neuroblastoma cells (2016)
  • Author(s): Mohammad Sazzadul Islam, Yasutoshi Tatsumi, Ryo Takano, Tomoki Yokochi, Jesmin Akter, Toshinori Ozaki, Yohko Nakamura, Miki Ohira, and Akira Nakagawara
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 478 Issue: 1 Pages: 81-86
  • DOI: 10.1016/j.bbrc.2016.07.089
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Depletion of pro-oncogenic RUNX2 enhances gemcitabine (GEM) sensitivity of p53-mutated pancreatic cancer Panc-1 cells through the induction of pro-apoptotic TAp63. (2016)
  • Author(s): Ozaki T, Nakamura M, Ogata T, Sang M, Yoda H, Hiraoka K, Sang M, Shimozato O.
  • Journal Title: Oncotarget Volume: 7 Issue: 44 Pages: 71937-71950
  • DOI: 10.18632/oncotarget.12433
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Silencing of RUNX2 enhances gemcitabine sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the stimulation of TAp63-mediated cell death. (2015)
  • Author(s): Sugimoto H, Nakamura M, Yoda H, Hiraoka K, Shinohara K, Sang M, Fujiwara K, Shimozato O, Nagase H, Ozaki T.
  • Journal Title: Cell Death Discovery Volume: 6 Issue: 10 Pages: e1914-e1914
  • DOI: 10.1038/cddis.2015.242
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Runt-related transcription factor 2 (RUNX2) attenuates the transcriptional activity as well as DNA damage-mediated induction of pro-apoptotic TAp73 to regulate chemo-sensitivity (2015)
  • Author(s): Ozaki T, Sugimoto H, Nakamura M, Hiraoka K, Yoda H, Sang M, Fujiwara K, Nagase H.
  • Journal Title: FEBS Journal Volume: 82 Issue: 1 Pages: 114-28
  • DOI: 10.1111/febs.13108
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Receptor-type protein tyrosine phosphatasedirectly dephosphorylates CD133 and regulates downstream AKT activation (2014)
  • Author(s): Shimozato O, Souda H
  • Journal Title: Oncogene Volume: 34(15) Issue: 15 Pages: 1-12
  • DOI: 10.1038/onc.2014.141
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate. (2014)
  • Author(s): Hiraoka K, Inoue T, Taylor RD, Watanabe T, Koshikawa N, Yoda H, Shinohara K, Takatori A, Sugimoto H, Maru Y, Denda T, Fujiwara K, Balmain A, Ozaki T, Bando T, Sugiyama H, Nagase H.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 6706-6706
  • DOI: 10.1038/ncomms7706
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] スフェア培養を用いたがん幹細胞が有する悪性形質獲得機構の解明 (2017)
  • Author(s): 下里修、早田浩明、松下雅司、内海京寛、森祐輔、筆宝義隆、永瀬浩喜、尾崎俊文
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台
• [Presentation] Comprehensive genetic analysis for the anticancer activity of a novel alkylating agent targeting KRAS mutation. (2016)
  • Author(s): K. Hiraoka, J. Lin, A. Takatori, A. Hattori, T. Inoue, H. Yoda, S. Krishnamurthy, Y. Shinozaki, T. Watanabe, N. Koshikawa, T. Ozaki, H. Nagase
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] RUNX2 depletion improves gemcitabine sensitivity of p53-mutated pancreatic cancer cells through stimulation of TAp73. (2016)
  • Author(s): M. Nakamura, H. Sugimoto, T. Ogata, M. Sang, O. Shimozato, T. Ozaki
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Internalization of DNA minor groove binder pyrrole-imidazole polyamide into cancer cells via actin-dependent mechanism. (2016)
  • Author(s): O. Shimozato, M. Matsushita, K. Uchiumi, M. Nakamura, T. Ogata, M. Sang, T. Inoue, T. Watanabe, H. Nagase, T. Ozaki:
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] PTPRKによるがん幹細胞マーカーCD133の脱リン酸化を介した大腸がん進展の抑制 (2016)
  • Author(s): 松下雅司、下里修、早田浩明、内海京寛、森祐輔、中村瑞代、小形武広、桑梅潔、尾崎俊文
  • Organizer: 第25回日本病態治療研究会
  • Place of Presentation: 千葉
• [Presentation] 進行神経芽腫に対するMYCN遺伝子標的ピロールイミダゾールポリアミドDNAアルキル化剤複合体の開発 (2015)
  • Author(s): 養田裕行、高取敦志、井上貴博、渡部隆義、越川信子、尾崎俊文、永瀬浩喜
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-10
• [Presentation] RUNX2の発現抑制を介したTAp63の活性化による膵臓がん細胞のゲムシタビン感受性の向上 (2015)
  • Author(s): 中村瑞代、杉本博一、小形武広、下里修、永瀬浩喜、尾崎俊文
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-10
• [Presentation] NLRR2 is involved in neuronal survival and differentiation through JNK pathway in neuroblastoma (2015)
  • Author(s): Afzal Sheikh,Atsushi Takatori,Md.Shamim Hossain,Md.Kamrul Hasan,Toshinori Ozaki ,Hiroki Nagase,Masatoshi Tagawa,Akira Nakagawara
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] KR12, KRAS mutation specific alkylating agent inhibits tumor growth by showing accumulation in KRAS mutant xenografts (2015)
  • Author(s): Takahiro Inoue,Kiriko Hiraoka,Hiroyuki Yoda,Takayoshi Watanabe,Atsushi Takatori,Nobuko Koshikawa,Toshikazu Bando,Hiroshi Sugiyama,Toshinori Ozaki, Hiroki Nagase
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 新規アルキル化剤: ピロールイミダゾールポリアミド複合体による変異型 KRAS の発現抑制 (2015)
  • Author(s): 平岡桐子、井上貴博、養田裕行、クリシュナムルティサクティスリ、ジェイソンリン、渡部隆義、越川信子、高取敦志、尾崎俊文、永瀬浩喜
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08