Role of PPARγ in the growth, differentiation and apoptosis of gastrointestinal epithelial cells.

PPARγ在胃肠道上皮细胞生长、分化和凋亡中的作用。

• 批准号: 11670502
• 负责人: MIYAZAKI Yoshiji
• 金额: $ 2.24万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670502/
• 关键词: PPARγ; HB-EGF; amphiregulin; cyclin D1; AP-1; Ets; growth; differentiation; 消化管上皮

Several colonic and gastric cancer cell lines express peroxisome proliferator activated receptor γ (PPARγ), a member of the nuclear receptor superfamily. The purpose of the present study was to clarify the role of PPARγ in the growth and differentiation of gastrointestinal epithelial cells and to evaluate the possibility that ligands for PPARγ can be effective for the treatment of gastrointestinal carcinoma.1. Activation of PPARγ inhibits the growth of HT-29 colonic cancer cells and induces the differentiation markers.2. Ligand activation of PPARγ reduces the expression of c-Met tyrosine kinase at the transcriptional level. This may be one mechanism, by which activation of PPARγ inhibits the growth of MKN-45 gastric cancer cells.3. We created a cell line, IECrasPR82 that expresses both oncogenic ras and PPARγ by DNA transfection. Activation of PPARγ inhibits the growth of this cell line.4. Ligands for PPARγ inhibit the expression of heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and cyclin D1 through the suppression of AP-1 and Ets.5. Thus PPARγ ligands may be candidates for a novel approach to the treatment of gastric and colorectal cancers.

几种结肠癌和胃癌细胞系表达核受体超家族成员过氧化物酶体增殖物激活受体γ（PPARγ）。本研究的目的是阐明过氧化物酶体增殖物激活受体γ（PPARγ）在胃肠道上皮细胞生长和分化中的作用，并探讨其配体治疗胃肠道肿瘤的可能性.激活PPARγ可抑制HT-29结肠癌细胞的生长，并诱导分化标志物的表达.配体激活的PPARγ在转录水平降低c-Met酪氨酸激酶的表达。这可能是激活PPARγ抑制MKN-45胃癌细胞生长的机制之一.我们建立了一个细胞系，IECrasPR 82，通过DNA转染表达致癌ras和PPARγ。激活PPARγ可抑制该细胞系的生长. PPARγ配体通过抑制AP-1和Ets抑制肝素结合EGF样生长因子（HB-EGF）、双调蛋白和细胞周期蛋白D1的表达。因此，PPARγ配体可能是治疗胃癌和结直肠癌的新方法的候选者。

项目成果

N.Sawada-Hase, T.Kiyohara, J.Miyagawa, H.Ueyama, H.Nishibayashi, Y.Murayama, T.Kashihara^*, M.Nakahara, Y.Miyazaki, R.Nezu^*, Y.Shinomura, Y.Matsuzawa: "An increased number of CD40-high monocytes in patients with Crohn's disease."Am.J.Gastroenterol.. 95(6

N.Sawada-Hase、T.Kiyohara、J.Miyakawa、H.Ueyama、H.Nishibayashi、Y.Murayama、T.Kashihara^*、M.Nakahara、Y.Miyazaki、R.Nezu^*、Y.Shinomura、

S.Kitamura, et.al.: "Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers."Br.J.Cancer. 83(5). 668-673 (2000)

S.Kitamura 等人：“Met/HGF 受体调节 bcl-w 表达并抑制人类结直肠癌的细胞凋亡。”Br.J.Cancer。

宮崎義司 他: "PPAR peroxisome proliferator-activated receptor"G.I.Research. 8. 80-81 (2000)

Yoshiji Miyazaki 等人：“PPAR 过氧化物酶体增殖物激活受体”G.I.Research. 8. 80-81 (2000)。

S.Kitamura, S.Kondo, Y.Shinomura, S.Kanayama, Y.Miyazaki, T.Kiyohara, S.Hiraoka, Y.Matsuzawa: "Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers."Br.J.Cancer. 83(5). 668-673 (2000)

S.Kitamura、S.Kondo、Y.Shinomura、S.Kanayama、Y.Miyazaki、T.Kiyohara、S.Hiraoka、Y.Matsuzawa：“Met/HGF 受体调节 bcl-w 表达并抑制人类结直肠癌细胞凋亡。

S.Kondo, Y.Shinomura, Y.Miyazaki, T.Kiyohara, S.Tsutsui, S.Kitamura, Y.Nagasawa, M.Nakahara, S.Kanayama, Y.Matsuzawa: "Mutations of the bak gene in human gastric and colorectal cancers"Cancer Res.. 60(16). 4328-4330 (2000)

S.Kondo、Y.Shinomura、Y.Miyazaki、T.Kiyohara、S.Ttsutsui、S.Kitamura、Y.Nagasawa、M.Nakahara、S.Kanayama、Y.Matsuzawa：“人类胃和胃中 bak 基因的突变