Roles and mechanisms of cellular senescence in cancer microenvironment

• Project Area: Integrative Research on Cancer Microenvironment Network
• Project/Area Number: 23112101
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: HARA Eiji 公益財団法人がん研究会, がん研究所がん生物部, 部長 (80263268)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥32,370,000 (Direct Cost: ¥24,900,000、Indirect Cost: ¥7,470,000); Fiscal Year 2014: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000); Fiscal Year 2013: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000); Fiscal Year 2012: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
• Keywords: 発がん / 細胞老化 / がん微小環境 / 液性因子 / 発癌 / 遺伝子 / 癌 / ゲノム / シグナル伝達 / 発現制御

Outline of Final Research Achievements

We have tried to understand the roles and mechanisms of senescent stromal cells in cancer microenvironment, and following findings are obtained : (1) In senescent cells, DNA damage response provokes degradation of G9a/GLP histone methyltransferases and thereby causing epigenetic de-repression of SASP factor genes. (2) Senescent hepatic stromal cells promote hepatocellular tumorigenesis through secreting SASP factors. (3) SASP primarily promotes tissue repair, contributing to maintenance of homeostasis. Excess amount and/or duration of SASP, however, provokes tumorigenesis.

Research Products

• [Journal Article] Evidence for a CDK4-dependent checkpoint in a conditional model of cellular senescence. (2015)
  • Author(s): Brookes S, Gagrica S, Sanij E, Rowe J, Gregory FJ, Hara E, and *Peters G.
  • Journal Title: Cell Cycle Volume: 14 Issue: 8 Pages: 1164-1173
  • DOI: 10.1080/15384101.2015.1010866
  • Peer Reviewed / Open Access
• [Journal Article] In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. (2015)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 106 Issue: 3 Pages: 244-52
  • DOI: 10.1111/cas.12600
  • NAID: 120005830611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dysregulation of the Bmi-1/p16Ink4a pathway provokes an aging-associated decline of submandibular gland function. (2015)
  • Author(s): Yamakoshi K, Katano S, Iida M, Kimura H, Okuma A, Ikemoto-Uezumi M, Ohtani N, Hara E, Maruyama M.
  • Journal Title: Aging Cell Volume: - Issue: 4 Pages: 1-9
  • DOI: 10.1111/acel.12337
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice. (2015)
  • Author(s): Sato, S., Kawamata, Y., Takahashi, A., Imai, Y., Hanyu, A., Okuma, A., Takasugi, M., Yamakoshi, K., Sorimachi, H., Kanda, H., Ishikawa, Y., Sone, S., Nishioka, Y., Ohtani, N., Hara, E.
  • Journal Title: Nature Communications Volume: 6:7035 Pages: 1-10
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Crosstalk between the RB-pathway and AKT signalling forms a Quiescence-Senescence switch. (2014)
  • Author(s): Imai, Y., Takahashi, A., Hanyuu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., Hara, E.
  • Journal Title: Cell Reports Volume: 7 Issue: 1 Pages: 194-207
  • DOI: 10.1016/j.celrep.2014.03.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Necessary and sufficient role for a mitosis skip in senescence induction. (2014)
  • Author(s): Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S, Nakanishi M.
  • Journal Title: Mol.Cell Volume: 55 Issue: 1 Pages: 73-84
  • DOI: 10.1016/j.molcel.2014.05.003
  • Peer Reviewed
• [Journal Article] An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. (2014)
  • Author(s): Demaria, M., Ohtani, N., Youssef, S.A., Rodier, F., Toussaint, W., Mitchell, J.R., Laberge, R.M., Vijg, J., Van Steeg, H., Dollé, M.E.T., Hoeijmakers, J.H.J., de Bruin, A., Hara, E.., Campisi, J.
  • Journal Title: Developmental Cell Volume: 31 Issue: 6 Pages: 722-733
  • DOI: 10.1016/j.devcel.2014.11.012
  • Peer Reviewed
• [Journal Article] Obesity and Cancer: a gut microbial connection (2014)
  • Author(s): Ohtani, N.
  • Journal Title: Cancer Research Volume: 74 Issue: 7 Pages: 1885-11889
  • DOI: 10.1158/0008-5472.can-13-3501
  • Peer Reviewed
• [Journal Article] Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome (2013)
  • Author(s): Yoshimoto, S.
  • Journal Title: Nature Volume: 499 Issue: 7456 Pages: 97-101
  • DOI: 10.1038/nature12347
  • Peer Reviewed
• [Journal Article] Ohtani N, Hara E. (2013)
  • Author(s): Roles and mechanisms of cellular senescence in regulation of tissue homeostasis.
  • Journal Title: Cancer Science Volume: 104 Issue: 5 Pages: 525-530
  • DOI: 10.1111/cas.12118
  • Peer Reviewed
• [Journal Article] Protein Kinase A Determines Timing of Early Differentiation through Epigenetic Regulation with G9a (2012)
  • Author(s): Yamamizu K, Fujihara M, Tachibana M, Katayama S, Takahashi A, Hara E, Imai H, Shinkai Y, and Yamashita JK
  • Journal Title: Cell Stem Cell Volume: 10 Issue: 6 Pages: 759-770
  • DOI: 10.1016/j.stem.2012.02.022
  • Peer Reviewed
• [Journal Article] Development of mice without Cip/Kip CDK inhibitors (2012)
  • Author(s): Tateishi Y., et al.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 427 Issue: 2 Pages: 285-292
  • DOI: 10.1016/j.bbrc.2012.09.041
  • Peer Reviewed
• [Journal Article] DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells (2012)
  • Author(s): Akiko Takahashi
  • Journal Title: Molecular Cell Volume: 45 Issue: 1 Pages: 123-131
  • DOI: 10.1016/j.molcel.2011.10.018
  • Peer Reviewed
• [Journal Article] E2FBP1 antagonizes the p16INK4A-Rb tumor suppressor machinery for growth suppression and cellular senescence by regulating promyelocytic leukemia protein stability (2011)
  • Author(s): Yayoi Fukuyo
  • Journal Title: International Journal of Oral Science Volume: 4 Issue: 4 Pages: 200-208
  • DOI: 10.4248/ijos11070
  • Peer Reviewed
• [Presentation] Gut microbiota and fatty liver disease (2015)
  • Author(s): Eiji Hara
  • Organizer: Gut microbiota for health world summit 2015
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2015-03-14 – 2015-03-15
  • Invited
• [Presentation] 肥満と肝がん：腸内細菌の関与について (2015)
  • Author(s): 原英二
  • Organizer: 泌尿器科分子細胞研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-02-27
  • Invited
• [Presentation] 肥満と肝がん：腸内細菌の関与について (2015)
  • Author(s): 原英二
  • Organizer: 酸化ストレスと肝研究会
  • Place of Presentation: 福岡
  • Year and Date: 2015-02-14 – 2015-02-15
  • Invited
• [Presentation] 細胞老化の発癌制御における役割 (2015)
  • Author(s): 原英二
  • Organizer: ヒューマンサイエンス総合研究セミナー
  • Place of Presentation: 東京
  • Year and Date: 2015-01-13
  • Invited
• [Presentation] Cellular senescence and cancer: a gut microbial connection (2015)
  • Author(s): Eiji Hara
  • Organizer: Joint international symposium on TGF-b family and cancer signal network in tumor microenvironment
  • Place of Presentation: つくば
  • Year and Date: 2015-01-12 – 2015-01-13
  • Invited
• [Presentation] Obesity and cancer: a gut microbial connection (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
  • Invited
• [Presentation] 細胞老化と発がん：腸内細菌の関与について (2014)
  • Author(s): 原英二
  • Organizer: 日本肥満学会
  • Place of Presentation: 宮崎
  • Year and Date: 2014-10-23 – 2014-10-24
  • Invited
• [Presentation] Relationship between obesity, gut microbiome and HCC development (2014)
  • Author(s): Eiji Hara
  • Organizer: Falk Gastro-Conference
  • Place of Presentation: Freiburg, Germany
  • Year and Date: 2014-10-08 – 2014-10-11
  • Invited
• [Presentation] Cross-talk between the Rb^pathway and AKT signaling forms a quiescence-senescence switch (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] 細胞老化と炎症 (2014)
  • Author(s): 原英二
  • Organizer: 日本動脈硬化学会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
  • Invited
• [Presentation] 細胞老化と炎症 (2014)
  • Author(s): 原英二
  • Organizer: 日本炎症再生医学会
  • Place of Presentation: 名護
  • Year and Date: 2014-07-01 – 2014-07-03
  • Invited
• [Presentation] The roles and mechanisms of cellular senescence (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本基礎老化学会
  • Place of Presentation: 大府
  • Year and Date: 2014-06-26 – 2014-06-27
  • Invited
• [Presentation] Obesity-induced gut microbial metabolite promotes liver cancer via senescence secretome (2014)
  • Author(s): Eiji Hara
  • Organizer: Cold Spring Harbor Asia Conference
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-05-19 – 2014-05-23
  • Invited
• [Presentation] 細胞老化と発がん (2014)
  • Author(s): 原英二
  • Organizer: 日本臨床分子医学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-12
  • Invited
• [Presentation] Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretom. (2014)
  • Author(s): Eiji Hara
  • Organizer: US-Japan Joint Meeting on Biomarkers for Early Cancer Detection.
  • Place of Presentation: Gaithersburg (USA)
  • Invited
• [Presentation] DNA damage response and cellular senescence in cancer (2013)
  • Author(s): Hara, E.
  • Organizer: 9th AACR-JCA joint conference
  • Place of Presentation: Maui, HI, (U.S.A.)
  • Year and Date: 2013-02-21
  • Invited
• [Presentation] 細胞老化のがん化と廊下における役割 (2013)
  • Author(s): 原 英二
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] DNA damage response and cellular senescence in cancer and aging. (2013)
  • Author(s): Eiji Hara
  • Organizer: International Conference of the Korean Society for Molecular and Cellular Biology
  • Place of Presentation: Seoul (South Korea)
  • Invited
• [Presentation] The roles of cellular senescence in cancer and aging. (2012)
  • Author(s): Hara, E.
  • Organizer: 日本分子生物学会
  • Place of Presentation: 福岡市
  • Year and Date: 2012-12-11
  • Invited
• [Presentation] Senescence-associated Secretory Phenotypes (SASPs) Promote Obesity-associated Hepatocarcinogenesis (2012)
  • Author(s): Ohtani, N.
  • Organizer: Keystone Symposium, Aging
  • Place of Presentation: 東京
  • Year and Date: 2012-10-22
• [Presentation] The roles and mechanisms regulating cellular (2012)
  • Author(s): Hara, E.
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌市
  • Year and Date: 2012-09-19
  • Invited
• [Presentation] Cellular senescence: a double-edged sword in the fight against cancer (2012)
  • Author(s): Hara, E.
  • Organizer: International Symposium on Clinical Translational Cancer Research
  • Place of Presentation: 高雄市 （台湾）
  • Year and Date: 2012-05-17
  • Invited
• [Presentation] 細胞老化の分子メカニズムとその生体内機能 (2012)
  • Author(s): 原 英二
  • Organizer: 日本生化学会関東支部会シンポジウム
  • Place of Presentation: 前橋市
  • Invited
• [Presentation] The roles and mechanisms regulating cellular senescence in aging and cancer (2011)
  • Author(s): Eiji Hara
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-14
• [Presentation] 細胞老化の分子機構とその役割 (2011)
  • Author(s): 原英二
  • Organizer: 日本血管生物医学会
  • Place of Presentation: 東京
  • Year and Date: 2011-12-10
• [Remarks]
  • URL: http://www.jfcr.or.jp/tci/canbio/index.html