Nuclear receptors as molecular regulator and chemopreventive targets of colon cancer stem cells.

• Project/Area Number: 23501324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cancer epidemiology and prevention
• Research Institution: Health Sciences University of Hokkaido
• Principal Investigator: MASUDA Sonoko 北海道医療大学, 薬学部, 教授 (90157206)
• Co-Investigator(Kenkyū-buntansha): TANAKA Takuji 岐阜大学, 医学部, 非常勤講師 (40126743) ; OSANAI Makoto 高知大学, 教育研究部・医療学系, 准教授 (60381266) ; TERASAKI Masaru 北海道医療大学, 薬学部, 講師 (10391195)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 大腸がん幹細胞 / 核内受容体 / がん化学予防 / 分子標的治療 / ビタミンD / カロテノイド / 分子イメージング / がん遺伝子 / 薬物代謝酵素 / がん幹細胞標的分子 / ビタミンＤ / フコキサンチノール / VDR / PPARG / RAR

Research Abstract

Increasing evidence suggests that colon cancer stem cells (CCSC) have responsible for carcinogenesis, cancer development and recurrence. To establish signaling pathways in CCSC, which are implicated in the initiation and progression of colon cancer, we examined nuclear receptor signaling in colonospheres that are enriched in CCSC from established cell lines. We found that colonospheres formed by colon cancer cell lines are highly enriched in CCSC and that Wnt/b-catenin pathway plays a critical role in growth and maintenance of colonospheres. We also found that the combination of Fucoxanthinol and 1a,25-dihydroxyvitamin D3 acts on the CCSC cell growth through down-regulation of PPARg and NFkB p52, and as an intrinsic factor for the prevention of colon cancer. These findings establish a critical role for PPARg and vitamin D receptor (VDR) in growth regulation in colon cancer cells via functionally relevant cross-talk between these nuclear signaling pathways.

Research Products

• [Journal Article] Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in <i>Apc</i>^Min/+ mice (2014)
  • Author(s): Shimizu S, Fujii G, Takahashi M, Nakanaishi R, Komiya M, Shimura M, Noma N, Onuma W, Yano T, Mutoh M.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 54 Issue: 2 Pages: 95-101
  • DOI: 10.3164/jcbn.13-91
  • NAID: 130004879356
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice (2013)
  • Author(s): Iguchi M, Osanai M, Hayashi Y, Koentgen F, Lee GH
  • Journal Title: Oncogene advance online publication Volume: 33 Issue: 27 Pages: 3612-3617
  • DOI: 10.1038/onc.2013.331
  • Peer Reviewed
• [Journal Article] Chemical-induced Carcinogenesis. (2013)
  • Author(s): Takuji Tanaka, Masahito Shimizu, Takahiro Kochi, and Hisataka Moriwaki
  • Journal Title: J. Exp. Clin. Med. Volume: 5 Issue: 6 Pages: 203-209
  • DOI: 10.1016/j.jecm.2013.10.009
  • Peer Reviewed
• [Journal Article] Enhanced development of azoxymethane-induced colonic preneoplastic lesions in hypertensive rats. (2013)
  • Author(s): Takahiro Kochi, Masahito Shimizu, Tomohiko Ohno, Atsushi Baba, Takafumi Sumi, Masaya Kubota, Yohei Shirakami, Hisashi Tsurumi, Takuji Tanaka, and Hisataka Moriwaki
  • Journal Title: Int. J. Mol. Sci. Volume: 14 Issue: 7 Pages: 14700-14711
  • DOI: 10.3390/ijms140714700
  • Peer Reviewed
• [Journal Article] Organomagnesium suppresses inflammation-associated colon carcinogenesis in male Crj: CD-1 mice. (2013)
  • Author(s): Kuno, T., Hatano, Y., Tomita, H., Hara, A., Hirose, Y., Hirata, A., Mori, H., Terasaki, M, Masuda, S., and Tanaka, T.
  • Journal Title: Carcinogenesis Volume: 34 Issue: 2 Pages: 361-369
  • DOI: 10.1093/carcin/bgs348
  • Peer Reviewed
• [Journal Article] Combined antiproliferative effect of dietary PPARγ suppressing lipids fucoxanthinol and 1α,25-dihydroxyvitamin D_3 in human colon cancer cells (2012)
  • Author(s): Terasaki M, Nagao A, Maeda H, Miyashita K, Masuda S
  • Journal Title: Carotenoid Sci Volume: 17 Pages: 40-43
  • URL: http://www.carotenoid.jp
  • Peer Reviewed
• [Journal Article] Animal models of carcinogenesis in inflamed colorectum : potential use in chemoprevention study (2012)
  • Author(s): Tanaka T
  • Journal Title: Curr Drug Targets Volume: 13 Pages: 1689-1697
  • Peer Reviewed
• [Journal Article] Development of an inflammation-associated colorectal cancer model and its application for research on carcinogenesis and chemoprevention. (2012)
  • Author(s): Tanaka, T.
  • Journal Title: Int. J. Inflam. Volume: 2012 Pages: 1-16
  • DOI: 10.1155/2012/658786
  • Peer Reviewed
• [Journal Article] Combined antiproliferative effect of dietary PPARγ suppressing lipids fucoxanthinol and 1α,25-dihydroxyvitamin D3 in human colon cancer cells. (2012)
  • Author(s): Terasaki, M., Nagao, A., Maeda, H., Miyashita, K., and Masuda, S.
  • Journal Title: Carotenoid Sci. Volume: 17 Pages: 40-43
  • Peer Reviewed
• [Journal Article] Animal models of carcinogenesis in inflamed colorectum: potential use in chemoprevention study. (2012)
  • Author(s): Tanaka, T.
  • Journal Title: Curr. Drug Targets Volume: 13 Pages: 1689-1697
  • Peer Reviewed
• [Presentation] CD44発現と大腸がん幹細胞形質の相関性 (2014)
  • Author(s): 寺崎将、増田園子
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
• [Presentation] Functional roles of Wnt/β-catenin pathway regulating growth and maintenance of colonospheres (2014)
  • Author(s): Masuda S, Inoue S, Ohmura Y, Ono M, Takagi K, Nakagawa M, Nakamura K, Mikami Y, Yamamoto S, Sawada K, Hamazaki Y, Maeda S, Terasaki M
  • Organizer: 4^<th> International Symposium on Carcinogenic Spiral
  • Place of Presentation: Sapporo
• [Presentation] CD44 発現と大腸がん幹細胞形質の相関性 (2014)
  • Author(s): 寺崎 将、増田園子
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
• [Presentation] : Functional roles of Wnt/β-catenin pathway regulating growth and maintenance of colonospheres. (2014)
  • Author(s): S. Masuda, S. Inoue, Y. Ohmura, M. Ono, K. Takagi, M. Nakagawa, K. Nakamura, Y. Mikami, S. Yamamoto, K. Sawada, Y. Hamazaki, S. Maeda, and M. Terasaki
  • Organizer: 4th International Symposium on Carcinogenic Spiral
  • Place of Presentation: Sapporo
• [Presentation] マウス大腸発癌に及ぼすデオキシコール酸の影響 (2014)
  • Author(s): 久野壽也、田中卓二、内木 綾、佐藤慎哉、鈴木周五、高橋 智
  • Organizer: 第30回日本毒性病理学会総会及び学術集会
  • Place of Presentation: 徳島
• [Presentation] Functional roles of CD44 and EpCAM in the development of colorectal cancer stem cells (2013)
  • Author(s): Terasaki M, Masuda S
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 4'-Geranyloxyferulic acid-LNAME suppresses inflammation-associated colorectal carcinogenesis in mice (2013)
  • Author(s): Tanaka T, Kochi T, Shimizu M, Sugie S, Moriwaki H
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Deoxycholic acid, secondary bile acid promotes AOM-induced colorectal carcinogenesis in distal colon of mice but not proximal colon (2013)
  • Author(s): Kuno T, Tanaka T, Takamatsu M, Hatano Y, Tomita H, Hirose Y, Hirata A, Hara A
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] ニコチンはレチノイン酸代謝酵素CYP26A1の発現を低下させ乳癌の進行を抑制する (2013)
  • Author(s): 小山内誠、李康弘
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 分子イメージングによるがん幹細胞の特性解析 (2013)
  • Author(s): 加藤雄也、工藤成美、佐藤永楽、佐藤隆太郎、舘岡さおり、近野優、西川亮太、田中耕太、寺崎将、増田園子
  • Organizer: 日本薬学会北海道支部第140回例会
  • Place of Presentation: 札幌
• [Presentation] Functional roles of CD44 and EpCAM in the development of colorectal cancer stem cells. (2013)
  • Author(s): Masaru Terasaki and Sonoko Masuda
  • Organizer: 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] : C57BL/KsJ-db/db-ApcMin/+ mice are useful model animals for investigating colorectal carcinogenesis associated with obesity and diabetes. (2013)
  • Author(s): Masaya Kubota, Hata Kazuya, Masahito Shimizu, Atsushi Baba, Tomohiko Ohno, Takahiro Kochi, Yohei Shirakami, Takuji Tanaka, Hisataka Moriwaki
  • Organizer: 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] 4’-Geranyloxyferulic acid-L-NAME suppresses inflammation-associated colorectal carcinogenesis in mice. (2013)
  • Author(s): Takuji Tanaka, Takahiro Kochi, Masahito Shimizu, Shigeyuki Sugie, and Hisataka Moriwaki
  • Organizer: 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] Deoxycholic acid, secondary bile acid promotes AOM-induced colorectal carcinogenesis in distal colon of mice but not proximal colon. (2013)
  • Author(s): Toshiya Kuno, Takuji Tanaka, Manabu Takamatsu, Yuichiro Hatano, Hiroyuki Tomita, Yoshinobu Hirose, Akihiro Hirata, and Akira Hara
  • Organizer: 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] 4’-Geranyloxyferulic acid-L-NAME suppresses inflammation-associated colorectal carcinogenesis in mice. (2013)
  • Author(s): Takuji Tanaka, Takahiro Kochi, Takayuki Mori, Masahito Shimizu, and Hisataka Moriwaki
  • Organizer: 第20回日本がん予防学会
  • Place of Presentation: 東京
• [Presentation] ヒト大腸がん幹細胞の単離と特性解析 (2013)
  • Author(s): 西川亮太、近野 優、舘岡さおり、佐藤隆太郎、佐藤永楽、工藤成美、加藤雄也、田中耕太、寺崎 将、増田園子
  • Organizer: 日本薬学会北海道支部第140回例会
  • Place of Presentation: 札幌
• [Presentation] Cancer stem cell標的薬の迅速評価法の開発 (2013)
  • Author(s): 田中耕太、加藤雄也、工藤成美、佐藤永楽、佐藤隆太郎、舘岡さおり、近野 優、西川亮太、寺崎 将、増田園子
  • Organizer: 日本薬学会北海道支部第140回例会
  • Place of Presentation: 札幌
• [Presentation] Fucoxanthinolによる大腸がん幹細胞アポトーシス誘導作用とそのメカニズム (2013)
  • Author(s): 寺崎 将、前多隼人、増田園子
  • Organizer: 日本ビタミン学会第65回大会
  • Place of Presentation: 東京
• [Presentation] Combined antiproliferative effect in dietary PPARγ regulating lipids against human colorectal cancer cells (2011)
  • Author(s): Terasaki M, Maeda H, Hosokawa M, Miyashita K, Masuda S
  • Organizer: International Society for Nutraceuticals and Functional Foods (ISNFF)
  • Place of Presentation: Sapporo
• [Presentation] フコキサンチンと活性型ビタミンD_3の複合効果による大腸がん化学予防法の開発 (2011)
  • Author(s): 寺崎将、長尾昭彦、前多隼人、宮下和夫、増田園子
  • Organizer: 第25回カロテノイド研究談話会
  • Place of Presentation: 筑波
• [Presentation] 機能性脂質によるPPARγ発現抑制 (2011)
  • Author(s): 寺崎将、増田園子
  • Organizer: 平成23年度がん若手研究者ワークショップ
  • Place of Presentation: 蓼科
• [Presentation] Combined antiproliferative effect in dietary PPARγ regulating lipids against human colorectal cancer cells. (2011)
  • Author(s): Masaru Terasaki, Hayato Maeda, Masahi Hosokawa, Kazuo Miyashita, Sonoko Masuda
  • Organizer: International Society for Nutraceuticals and Functional Foods (ISNFF)
  • Place of Presentation: Sapporo
• [Presentation] Organomagnesium suppresses inflammation-associated colon carcinogenesis in male Crj: CD-1 mice. (2011)
  • Author(s): Kuno Toshiya, Hiroyuki, Tomita, Yuichiro Hatano, Akira Hara, Hideki Mori, Masaru Terasaki, Sonoko Masuda, Takuji Tanaka
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association,
  • Place of Presentation: Nagoya
• [Presentation] フコキサンチンと活性型ビタミンD3による複合的大腸がん細胞増殖抑制の作用解析 (2011)
  • Author(s): 寺崎 将, 長尾昭彦, 田中卓二, 細川雅史, 宮下和夫, 増田園子
  • Organizer: 日本ビタミン学会第63回大会
  • Place of Presentation: 広島
• [Presentation] ヒト大腸がん幹細胞様細胞の同定とその性質
  • Author(s): 寺崎 将, 太田友子, 近藤雄介, 寺嶋 望, 中島聖太, 南 寿憲, 安田友香, 太田史子, 前多隼人, 増田園子
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] A highly polar xanthophyll of fucoxanthinol induces apoptosis in colonospher.
  • Author(s): Masaru Terasaki, and Sonoko Masuda
  • Organizer: The 71th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo
• [Presentation] PPARγ抑制によるフコキサンチノールの大腸がん細胞増殖抑制効果
  • Author(s): 寺崎 将, 前多隼人, 増田園子
  • Organizer: 日本ビタミン学会第64回大会
  • Place of Presentation: 岐阜
• [Presentation] ホウレン草由来 9’-cis-Neoxanthinによる大腸がん細胞増殖抑制作用機序
  • Author(s): 寺崎 将, 太田友子, 太田史子, 近藤雄介, 寺嶋 望, 中島聖太, 南 寿憲, 安田友香, 増田園子
  • Organizer: 日本薬学会北海道支部第138回例会
  • Place of Presentation: 札幌
• [Remarks] 研究室のホームページ
  • URL: http://www3.hoku-iryo-u.ac.jp/courses/1/010/index.html