PPARγリガンドを用いた大腸化学発癌予防の研究

2006 Fiscal Year Annual Research Report

• Project/Area Number: 18390222
• Research Institution: Yokohama City University
• Principal Investigator: 中島 淳 横浜市立大学, 医学研究科, 准教授 (30326037)
• Co-Investigator(Kenkyū-buntansha): 稲森 正彦 横浜市立大学, 医学部, 助手 (10381477) ; 阿部 泰伸 横浜市立大学, 医学部, 助手 (10347312)
• Keywords: PPARγ / 大腸癌 / アディポネクチン

Research Abstract

核内受容体型転写因子であるPPARγは脂肪細胞や大腸癌細胞などに多く発現しており,大腸癌細胞では細胞増殖抑制・分化誘導・アポトーシス誘導作用などが明らかにされている.われわれはこれまでPPARγリガンドがNF-κB活性を抑制し腸管の炎症を抑え,アゾキシメタン化学発癌モデルマウスにおいて発癌を抑制し,PPARγ阻害剤が培養癌細胞の増殖を抑制することを発見した.さらに大腸癌と関連が指摘されている肥満や糖尿病など生活習慣病の因子と拡大内視鏡により観察したヒトACFとの相関を検討し,ACFをメルクマールとしたPPARγリガンドの作用解析を検討した.下部消化管内視鏡検査を行った101例に対しACFを観察し問診,採血,腹部CT検査を行い,ACFの個数と各因子との相関を解析したところACFと肥満,特に内臓脂肪型肥満は特に強い相関を認めた.このメカニズムとして内臓脂肪の分泌するアディポネクチンなどのアディポサイトカインの関与,さらにこれらが細胞増殖に積極的に関与している可能性が示唆された.他方,免疫組織学的検討においては大腸正常粘膜に発現を認めたアディポネクチンが腺腫・癌において低下する傾向を発見しており内臓脂肪の分泌するアディポネクチンが大腸発癌に関与することが示唆された.また同意の得られた20症例に対し1〜8ヶ月間PPARγリガンドを投与したところACFが減少する傾向を認めた.一般に大腸癌化学発癌予防は癌の発生・消失をメルクマールに行うため長い時間と費用を必要とする研究になるが,与えられた短期間で臨床研究成果を出すためACFを用いたのは大変有用であった.またACFは大腸前癌病変と考えられておりこれが内臓脂肪型肥満など生活習慣病と関連することから,これらメカニズムの詳細な解析が大腸癌の罹患率・死亡率を低下しうることが示唆された.

Research Products

• [Journal Article] Differntial expression of peroxisome proliferators-activated receptor in histrologically different human gastric cancer tisues. (2006)
  • Author(s): Nomura S, Nakajima A, Ishimine S, Matsuishi N, Kadowaki T, Kaminishi M
  • Journal Title: J Exp Clin Cancer Res. 25 Pages: 4438
• [Journal Article] PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma, PPARdelta and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. (2006)
  • Author(s): Schaefer KL, Takahashi H, Morales VM, Harris G, Barton s, Osawa E, Nakajima A, Saubermann LJ.
  • Journal Title: Intl J Cancer. 120(3) Pages: 702-13
• [Journal Article] Inhibition of peroxisome proliferators-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties. (2006)
  • Author(s): Hirokazu Takahashi, Kouji Fujita, Toshio Fujisawa, Kyoko Yonemitsu, Ayako Tomimoto, Ikuko Ikeda, Masato Yoneda, Katherine Schaefer, Lawrence J Saubermann, Takeshi Shimamura, Satoru Saitoh, Masashi Tachibana, Koichiro Wada, Hitoshi Nakagama, Atsushi Nakajima
  • Journal Title: Cancer Sci. 97(9) Pages: 4906-9
• [Journal Article] Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation (2006)
  • Author(s): Koichiro Wada, Makoto Arita, Atsushi Nakajima, Kazufumi Katayama, Chiho Kudo, Yoshinori Kamisaki, Charles N. Serhan
  • Journal Title: The FASEB Journal 06 Pages: 1785-1792
• [Journal Article] Identification of ROBO1 as a novel hepatocellular carcinoma antigen and a potential therapeutic and diagnostic target. (2006)
  • Author(s): Ito H, Funahashi S, Yamauchi N, Shibahara J, Midorikawa Y, Kawai S, Kinoshita Y, Watanave A, Hippo Y, Ohtomo T, Iwanari H, Nakajima A, Makuuchi M, Fukayama M, Hirata Y, Hamakubo T, Kodama T, Tsuchiya M, Aburatani H.
  • Journal Title: Clin Cancer Res. 12(11 Pt 1) Pages: 3257-64
• [Journal Article] Blastocystis hominis infection in patient with regular dialysis. (2006)
  • Author(s): Hayashi M, Inamori M, Goto k, Akiyama T, Fujita K, Ikeda I, Fujisawa T, Takahashi H, Yoneda M, Hara K, Abe Y, Kirikoshi H, Kubota K, Saito S, Ueno N, Nakajima A, Hamada Y, fukutomi H, Satsuta H.
  • Journal Title: J Gastroenterol. 41(6) Pages: 605-6
• [Journal Article] Peroxisome Proliferator-activated Receptor y-mediated Regulation of Neural Stem Cell Proliferation and Differentiation. (2006)
  • Author(s): Koichiro Wada, Atsushi Nakajima, Katayama Kazufumi, Chiho Kudo, Atsuhiro Shibuya, Naoto Kubota, Yasuo, Terauchi, Masashi tachibana, Hiroyuki Miyoshi, Yoshinori Kamisaki, Tadanori Mayumi, Takashi Kadowaki, Richard S. Blumberg.
  • Journal Title: Journal of Biological Chemistry 18 Pages: 12673-81
• [Journal Article] Pleural Effusions following Endoscopic Injection Sclerotherapy for Cirrhotic Patients with Exophageal Varices (2006)
  • Author(s): Hideyuki Kayama, Masahiko Inamori, Jun-Ichi Togawa, Takeshi Shimamura, Yoko Tokita, Tadashi Umezawa, Takashi Sakaguchi, Makoto Naitoh, ajime Nagase, Atsushi Nakajima, Toshifumi Saito, Shizuo Tominaga, Norio Ueno, Katsuaki Tanaka, Hisahiko Sekihara
  • Journal Title: Hepato-Gastroenterology 53 Pages: 376-380
• [Journal Article] mRNA Expression of Inducible Nitric Oxide Synthase, Endothelial Nitric Oxide Synthase and Vascular Endothelial growth Gactor in Exophageal Mucosa Biopsy Specimens from Patients with Reflux Exophagitis (2006)
  • Author(s): Masahiko Inamori, Takeshi Shimamura, Hajime Nagase, Yasunobu Abe, Tadashi Umezawa, Atsushi akajima, Toshifumi Saito, Norio Ueno, Katsuaki Tanaka, Hisahiko Sekihara, Jun-ichi Togawa, Hiroki Kaifu, Hideo Tsuboi, Hideyuki Kayama, Shizuo tominaga.
  • Journal Title: Hepato-Gastroenterology 53 Pages: 361-365
• [Journal Article] Predominant T helper type 2-inflammatory responses promote murine colon cancers (2006)
  • Author(s): Osawa E, Nakajima A, Fujisawa T, Kawamura YI, Toyama-Sorimachi N, Nakagama H, Dohi-T.
  • Journal Title: Int J. Cancer. 118(9) Pages: 2232-6
• [Journal Article] Relationship between the serum concentrations of C-reactive protein and parameters of adiposity and insulin resistance in patients with type2 diabetes mellitus (2006)
  • Author(s): Iwasaki T, Nakajima A, Yoneda M, Terauchi Y.
  • Journal Title: Endocr J. 53(3) Pages: 345-56
• [Journal Article] Gastrointestinal : rectal polyp associated with schistosomiasis. (2006)
  • Author(s): Abe Y, Inamori M, Fujita K, Fujisawa T, Fujisawa N, Yoneda M, Takahashi H, Ikeda T, Hara K, Akiyama T, Kawamura H, Kato A, Kirikoshi H, Kobayashi N, Kubota K, Saito S, Sasaki T, Inayama Y, Ueno N, Nakajima A.
  • Journal Title: J Gastroenterol Hepatol. 21(7) Pages: 1216
• [Journal Article] Gastrointestinal : Gastrointestinal metastases from malignant melanoma. (2006)
  • Author(s): Inamori M, Ueno N, Fujita K, Fujisawa N, Yoneda M, Takahashi H, Ikeda T, Kawamura H, Abe Y, Kato A, Kirikoshi H, Kobayashi N, Shimamura T, Kubota K, Saito S, Sakaguchi T, Yamanaka S, Inayama Y, Nakajima A.
  • Journal Title: J Gastroenterol Hepatol. 21 Pages: 327
• [Journal Article] Evaluation of postprandial 3 h pH monitoring for gastroesophageal reflux disease-is there a possibility of streamlining the 24h test? (2006)
  • Author(s): Inamori M, Akiyama T, Akimoto K, Takahashi H, Abe Y, Nakajima A
  • Journal Title: J Gastroenterol Hepatol. 21(11) Pages: 1751-2
• [Journal Article] Undifferentiated spindle-cell carcinoma of the gallbladder : an immunohistochemical study. (2006)
  • Author(s): Kubota K, Kakuta Y, Kawamura s, Abe Y, Inamori M, Kawamura H, Kirikoshi H, Kobayashi N, Saito S, Nakajima A.
  • Journal Title: J Hepatobiliary Pncreat Surg. 13(5) Pages: 468-71
• [Journal Article] SHP1 Phosphatase-Dependent T Cell Inhibition by CEACAM1 Adhesion Molocule Isoforms. (2006)
  • Author(s): Nagaishi T, Pao L, Lin SH, Iijima H, Kaser A Qiao SW, Chen Z, Glickman J, Najjar SM, Nakajima A, Neel BG, Blumberg RS
  • Journal Title: Immunity. 209(Pt22) Pages: 4574-9
• [Journal Article] Role of CEACAM1 as a regulator of T cells. (2006)
  • Author(s): Nagaishi T, Iijima H, Nakajima A, Chen D, Blumberg RS.
  • Journal Title: Ann NY Acad Sci. Aug Pages: 1072-75