Controling cancer development by reprogramming technique

• Project/Area Number: 26460468
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tohoku University
• Principal Investigator: Horii Akira 東北大学, 医学系研究科, 教授 (40249983)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵がん / がん幹細胞 / リプログラミング / 増殖抑制 / EMT / 薬剤耐性 / 細胞遊走能 / 増殖制御 / がん

Outline of Final Research Achievements

Reprogramming mediated control of pancreatic cancer cell lines were attempted in this study. Four Yamanaka factors were introduced into pancreatic cancer cell lines PK-8 and PK-9 as well as their derived gemcitabine (GEM herein after) resistant cell lines RPK-8 and RPK-9. Lentivirus vector was first used but results were not successful. We next tried TET-vector but results were not successful. However, we observed some unexpected interesting findings. GEM resistance in RPK-9 is caused by homozygous deletion of DCK that is essential for activation of GEM. Hence, RPK-9 can survive under very high concentration of GEM. On the other hand, RPK-8 can survive under low concentration of GEM but cannot survive under very high concentration. Furthermore, upregulation of genes associated with stemness and EMT were evident in RPK-8. Cell motility was also upregulated. These results may suggest that stemness associated with EMT is playing an important role in acquisition of GEM in RPK-8.

Research Products

• [Int'l Joint Research] フロリダ大学(米国)
• [Journal Article] NDRG2, suppressed expression associates with poor prognosis in pancreatic cancer, is hypermethylated in the second promoter in human gastrointestinal cancers. (2017)
  • Author(s): Yamamura A, Miura K, Karasawa H, Motoi F, Mizuguchi Y, Saiki Y, Fukushige S, Sunamura M, Shibata C, Unno M, Horii A.
  • Journal Title: Biochem Biophys Res Commun Volume: 484 Issue: 1 Pages: 138-143
  • DOI: 10.1016/j.bbrc.2017.01.055
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ABCB1 Is Upregulated in Acquisition of Taxane Resistance: Lessons from Esophageal Squamous Cell Carcinoma Cell Lines (2016)
  • Author(s): Wang R, Sumarpo A, Saiki Y, Chen N, Sunamura M, Horii A.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 240 Issue: 4 Pages: 295-301
  • DOI: 10.1620/tjem.240.295
  • NAID: 130005179373
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeted TET oxidase activity through methyl-CpG-binding domain extensively suppresses cancer cell proliferation. (2016)
  • Author(s): Mizuguchi Y, Saiki Y, Horii A, Fukushige S.
  • Journal Title: Cancer Med Volume: 5 Issue: 9 Pages: 2522-2533
  • DOI: 10.1002/cam4.830
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 膵癌におけるマイクロサテライト不安定性（MSI）解析 (2016)
  • Author(s): 堀井明
  • Journal Title: 胆と膵 Volume: 37 Pages: 803-806
• [Journal Article] Acquisition of chemoresistance to gemcitabine is induced by a loss-of-function missense mutation of DCK. (2015)
  • Author(s): Nakano T, Saiki Y, Kudo C, Hirayama A, Mizuguchi Y, Fujiwara S, Soga T, Sunamura M, Matsumura N, Motoi F, Unno M, Horii A.
  • Journal Title: Biochem Biophys Res Commun Volume: 464 Issue: 4 Pages: 1084-1089
  • DOI: 10.1016/j.bbrc.2015.07.080
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Technological advances in epigenomics lead to a better understanding of inflammatory diseases, decitabine and H3K27me3. (2015)
  • Author(s): Fukushige S, Horii A
  • Journal Title: Epigenomics Volume: 7 Issue: 2 Pages: 133-136
  • DOI: 10.2217/epi.14.90
  • Peer Reviewed
• [Journal Article] Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension. (2015)
  • Author(s): Matsuo S, Saiki Yu, Adachi O, Kawamoto S, Fukushige S, Horii A, Saiki Yo
  • Journal Title: J Thorac Cardiovasc Surg Volume: 149 Issue: 3 Pages: 902-909
  • DOI: 10.1016/j.jtcvs.2014.10.030
  • Peer Reviewed
• [Journal Article] Characterization of functional transient receptor potential melastatin 8 (TRPM8) channels in human pancreatic ductal adenocarcinoma cells. (2014)
  • Author(s): Cucu D, Chiritoiu G, Petrescu S, Babes A, Stanica L, Duda DG, Horii A, Dima SO, Popescu I.
  • Journal Title: Pancreas Volume: in press Issue: 5 Pages: 795-800
  • DOI: 10.1097/mpa.0000000000000106
  • Peer Reviewed
• [Journal Article] Clinicopathological study of SDHB mutation-related pheochromocytoma and sympathetic paraganglioma. (2014)
  • Author(s): Kimura N, Takekoshi K, Horii A, Morimoto R, Imai T, Oki T, Saito T, Midorikawa S, Arao T, Sugisawa C, Yamada M, Otuka Y, Kurihara I, Sugano K, Nakane M, Fukuuchi A, Kitamoto T, Saitoh J, Nishikawa T, Naruse M.
  • Journal Title: Endocr Relat Cancer Volume: 21 Issue: 3 Pages: L13-L16
  • DOI: 10.1530/erc-13-0530
  • Peer Reviewed
• [Journal Article] S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility. (2014)
  • Author(s): Chen N, Sato D, Saiki Y, Sunamura M, Fukushige S, Horii A.
  • Journal Title: Biochem Biophys Res Commun Volume: in press Issue: 3 Pages: 459-464
  • DOI: 10.1016/j.bbrc.2014.04.025
  • Peer Reviewed
• [Journal Article] Highlights from the latest articles in epigenomics. (2014)
  • Author(s): Fukushige S, Horii A
  • Journal Title: Epigenomics Volume: 6(2) Issue: 2 Pages: 171-173
  • DOI: 10.2217/epi.14.2
  • Peer Reviewed
• [Journal Article] Diversity of microflora in colonic mucus from severe ulcerative colitis patients analyzed by terminal restriction fragment length polymorphism and clone libraries of bacterial 16S rRNA gene sequences. (2014)
  • Author(s): Huang IN, Sato Y, Sakamoto M, Ohkuma M, Ohnuma S, Naitoh T, Shibata C, Horii A, Nishimura J, Kitazawa H, Saito T
  • Journal Title: Adv Microbiol Volume: 4 Issue: 13 Pages: 857-870
  • DOI: 10.4236/aim.2014.413095
  • Peer Reviewed
• [Presentation] DNA hypermethylation of IRX4 is a frequent event that may confer growth advantage to pancreatic cancer cells. (2016)
  • Author(s): Shinichi Fukushige, Kanchan Chakma, Fuyuhiko Motoi, Michiaki Unno, Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Upregulation of S100A10 is associated with poor prognosis in lung adenocarcinoma (2016)
  • Author(s): Yuriko Saiki, Masaki Makita, Kazumori Arai, Akira Sakurada, Yoshinori Okada, Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Functional inactivation of DCK plays an important role for acquisition of gemcitabine resistance. (2016)
  • Author(s): Yuriko Saiki, Tomohiro Nakano, Akiyoshi Hirayama, Tomoyoshi Soga, Makoto Sunamura, Fuyuhiko Motoi, Michiaki Unno, Akira Horii
  • Organizer: 日本病理学会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-05-12
• [Presentation] Upregulation of S100A10 is associated with poor prognosis in lung cancer (2016)
  • Author(s): Masaki Makita, Yuriko Saiki, Kazumori Arai, Akira Sakurada, Yoshinori Okada, Akira Horii
  • Organizer: 日本病理学会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-05-12
• [Presentation] Targeted TET oxidase activity through methyl-CpG binding domain extensively suppresses cancer cell proliferation (2016)
  • Author(s): Shinichi Fukushige, Yasuhiko Mizuguchi, Kanchan Chakma, Yuriko Saiki, Akira Horii
  • Organizer: American Association for Cancer Research
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Targeted TET oxidase activity through methyl-CpG binding domain extensively suppresses cancer cell proliferation (2016)
  • Author(s): Shinichi Fukushige, Yasuhiko Mizuguchi, Kanchan Chakma, Yuriko Saiki, Akira Horii
  • Organizer: International Congress of Human Genetics
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Functional inactivation of DCK plays an important role for acquisition of gemcitabine resistance (2016)
  • Author(s): Yuriko Saiki, Tomohiro Nakano, Akiyoshi Hirayama, Tomoyoshi Soga, Makoto Sunamura, Fuyuhiko Motoi, Michiaki Unno, Akira Horii
  • Organizer: Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics
  • Place of Presentation: Maui（アメリカ合衆国）
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] Methyl-CpG targeted transcriptional activation (MeTA) induces apoptosis in LNCaP human prostate cancer cells by reactivating hypermethylated genes (2016)
  • Author(s): Toshiya Miyauchi, Akira Horii, and Shinichi Fukushige
  • Organizer: Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics
  • Place of Presentation: Maui（アメリカ合衆国）
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] Upregulation of S100A10 is associated with poor prognosis in lung cancer (2016)
  • Author(s): Masaki Makita, Yuriko Saiki, Akira Sakurada, Yoshinori Okada, Akira Horii
  • Organizer: Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics
  • Place of Presentation: Maui（アメリカ合衆国）
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] Clinical Utility of Patient Derived Xenografts to Determine Biomarkers of Prognosis and Map Resistance Pathways in EGFR-Mutant Lung Adenocarcinoma (2015)
  • Author(s): Kota Ishizawa, Erin L. Stewart, Celine Mascaux, Shingo Sakashita, Jenna Sykes, Ghassan Allo, Chang-Qi Zhu, Ming Li, Melania Pintilie, Igor Jurisica, Benjamin G. Neel, Ming-Sound Tsao, Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-08
• [Presentation] ABCB1 in side populations is a key ABC transporter essential for acquired taxane-chemoresistance in esophageal cancer cells (2015)
  • Author(s): Yuriko Saiki, Kota Ishizawa, Makoto Sunamura, Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-08
• [Presentation] DNMT-independent reactivation of hypermethylated genes induces growth suppression and apoptosis in LNCaP cells. (2015)
  • Author(s): Shinichi Fukushige, Toshiya Miyauchi, Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-08
• [Presentation] Human cancer cells acquire chemoresistance to gemcitabine mainly through loss-of-function mutations in the DCK gene (2015)
  • Author(s): Akira Horii, Yuriko Saiki, Tomohiro Nakano, Chiharu Kudo, Makoto Sunamura
  • Organizer: アメリカ癌学会
  • Place of Presentation: フィラデルフィア（アメリカ合衆国）
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] Molecular characterization of oncogenic properties of S100A4 in pancreatic and lung cancers, and identification of PRDM2 and IFI27 as the candidate downstream genes. (2014)
  • Author(s): Akira Horii, Na Chen, Hitoshi Sekine, Nobukazu Tsukamoto, Takahiro Tabata, Yuriko Saiki, Shinichi Fukushige, Makoto Sunamura
  • Organizer: American Society of Human Genetics
  • Place of Presentation: San Diego Convention Center, USA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] S100A4 is frequently overexpressed in lung cancer cells and promotes cell motility (2014)
  • Author(s): Na Chen, Yuriko Saiki, Makoto Sunamura, Shinichi Fukushige, Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜、みなとみらい
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Acquisition of chemoresistance to gemcitabine was caused by a loss-of-function missense mutation in deoxycytidine kinase gene in a human gastric cancer cell line (2014)
  • Author(s): Yuriko Saiki, Akiyoshi Hirayama, Masahiro Sugimoto, Tomoyoshi Soga, Makoto Sunamura, Fuyuhiko Motoi, Michiaki Unno, and Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜、みなとみらい
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Methyl-CpG targeted DNA demethylation by TET hydroxylase activity suppresses the growth of cancer cells. (2014)
  • Author(s): Shinichi Fukushige, Yuriko Saiki, and Akira Horii
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜、みなとみらい
  • Year and Date: 2014-09-25 – 2014-09-27
• [Remarks] Department of Molecular Pathology
  • URL: http://www.molpath.med.tohoku.ac.jp/
• [Remarks] 分子病理学分野
  • URL: http://www.med.tohoku.ac.jp/org/medical/13/index.html