Study of obesity-associated carcinogenesis and its application to cancer prevention

• Project/Area Number: 26250028
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka University (2015-2016); Japanese Foundation for Cancer Research (2014)
• Principal Investigator: Hara Eiji 大阪大学, 微生物病研究所, 教授 (80263268)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥38,350,000 (Direct Cost: ¥29,500,000、Indirect Cost: ¥8,850,000); Fiscal Year 2016: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000); Fiscal Year 2015: ¥12,610,000 (Direct Cost: ¥9,700,000、Indirect Cost: ¥2,910,000); Fiscal Year 2014: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
• Keywords: 細胞老化 / 肥満 / 腸内細菌 / 発がん / 癌 / 遺伝子 / 微生物

Outline of Final Research Achievements

We have previously shown that increased level of DCA, a secondary bile acid, contributes to liver cancer development in obese mice. However, the precise mechanisms underlying this phenomenon remain unclear. In this study, following findings are obtained: (1) obesity increases the levels of cholesterols and thereby causing production of bile acid. Because high level of bile acid is toxic for many gut bacteria, gut bacteria which are resistant to bile acid, such as secondary bile acid producing bacteria, are preferentially increased in obese mice, resulting in alteration of gut bacterial community in obese mice. (2) Although DCA on its own can provoke senescence-associated secretary phenotype (SASP) in hepatic stellate cells (HSCs) in lean mice, it takes a much longer time as compared to those in obese mice. Here, we show that DCA cooperates with Lipoteichoic acid (LTA), to provoke the onset of SASP in HSCs through toll-like receptor 2 signaling pathway in obese mice.

Research Products

• [Journal Article] Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. (2017)
  • Author(s): Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, Nakajima-Takagi Y, Iwama A, Koga T, Sugimoto Y, Ozawa T, Nakamura M, Kumagai M, Watashi K, Taketo M, Aoki T, Narumiya S, Oshima M, Arita M, Hara E, Ohtani N.
  • Journal Title: Cancer Discov Volume: in press Issue: 5 Pages: 522-538
  • DOI: 10.1158/2159-8290.cd-16-0932
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of SASP and its potential as a therapeutic target for senescence-associated diseases. (2017)
  • Author(s): Watabnabe, S., Kawamoto, S., Ohtani, N., & Hara, E.
  • Journal Title: Cancer Science Volume: - Issue: 4 Pages: 563-569
  • DOI: 10.1111/cas.13184
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exosomes maintain cellular homeostasis by excreting harmful DNA from cells (2017)
  • Author(s): Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M.T., Obuse, C. & Hara, E.
  • Journal Title: Nature Communications Volume: - Issue: 1 Pages: 15287-15287
  • DOI: 10.1038/ncomms15287
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice (2015)
  • Author(s): Seidai Sato, Yuka Kawamata, Akiko Takahashi, Yoshinori Imai, Aki Hanyu, Atsushi Okuma, Masaki Takasugi, Kimi Yamakoshi, Hiroyuki Sorimachi, Hiroaki Kanda, Yuichi Ishikawa, Saburo Sone, Yasuhiko Nishioka, Naoko Ohtani and Eiji Hara
  • Journal Title: Nature communications Volume: 6 Issue: 1 Pages: 7035-7035
  • DOI: 10.1038/ncomms8035
  • 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] 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] 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] 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] 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
• [Presentation] 腸内細菌による発がん制御 (2016)
  • Author(s): 原 英二
  • Organizer: 日本臨床栄養学会
  • Place of Presentation: 大阪市
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] Obesity and cancer : a gut microbial connection (2016)
  • Author(s): Eiji Hara
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] Cellular senescence and liver cancer : a gut microbial connection (2016)
  • Author(s): Eiji Hara
  • Organizer: FASEB Conference, Liver Biology
  • Place of Presentation: West palm beach, FL, USA
  • Year and Date: 2016-06-26
  • Int'l Joint Research / Invited
• [Presentation] Obesity, the gut microbiome and liver cancer (2016)
  • Author(s): Eiji Hara
  • Organizer: EASL The International Liver Congress
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-04-13
  • Int'l Joint Research / Invited
• [Presentation] Obesity and cellular senescence: a gut microbial connection (2015)
  • Author(s): Eiji Hara
  • Organizer: International Cell Senescence Association Conference
  • Place of Presentation: Santiago de Compostela, Spain
  • Year and Date: 2015-07-19
  • Int'l Joint Research / Invited
• [Presentation] Obesity and Cellular Senescence: a gut microbial connection (2015)
  • Author(s): Eiji Hara
  • Organizer: EMBO Workshop Developmental Circuits in Aging
  • Place of Presentation: Crete, Greece
  • Year and Date: 2015-05-25
  • Int'l Joint Research / Invited
• [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] Obesity and cancer: a gut microbial connection (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本免疫学会
  • Place of Presentation: 京都市
  • Year and Date: 2014-12-10 – 2014-12-12
  • Invited
• [Presentation] The roles of cellular senescence in aging and cancer (2014)
  • Author(s): Akiko Takahashi, Eiji Hara
  • Organizer: 日本分子生物学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] 細胞老化と発癌：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: 宮崎市
  • Year and Date: 2014-10-23 – 2014-10-25
  • Invited
• [Presentation] 細胞老化反応の生体内イメージング (2014)
  • Author(s): 大熊敦史、大谷直子、山越貴水、原 英二
  • Organizer: 日本生化学会
  • Place of Presentation: 京都市
  • Year and Date: 2014-10-15 – 2014-10-17
  • 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] Crosstalk 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: 神奈川県横浜市
  • 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: 2014-07-11 – 2014-07-12
  • 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: 沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-03
  • Invited
• [Presentation] The roles and mechanisms of cellular senescence (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本基礎老化学会国際シンポジウム
  • Place of Presentation: 愛知県大府市
  • 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] 細胞老化と発癌 (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 – 2014-04-13
  • Invited
• [Remarks] 大阪大学微生物病研究所原研究室
  • URL: http://www.biken.osaka-u.ac.jp/lab/molmicro/
• [Remarks] 原 英二 研究室 ホームページ
  • URL: http://www.biken.osaka-u.ac.jp/lab/molmicro/