INVOLVEMENT OF MEMBRANE-TYPE BILE ACID RECEPTOR M-BAR/TGR5 IN BILE ACID-INDUCED ACTIVATION OF EPIDERMAL GROWTH FACTOR RECEPTOR AND MITOGEN-ACTIVATED PROTEIN KINASES IN GASTRIC CARCINOMA CELLS.

膜型胆汁酸受体 M-BAR/TGR5 参与胆汁酸诱导的胃癌细胞表皮生长因子受体和丝裂原激活蛋白激酶的激活。

• 批准号: 17590680
• 负责人: YASUDA Hiroshi
• 金额: $ 1.15万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590680/
• 关键词: bile acids; EGF receptor; M-BAR; TGR5; GPCR; ADAM

Bile acids, which have been implicated in carcinogenesis of the gastrointestinal tract, share properties of tumor promoters in that both affect cell signal-transduction pathways responsible for cell proliferation. The results of several studies suggest that mitogen-activated protein kinase activation is involved in the cellular effects of bile acids. In the present study, we demonstrate that treatment of AGS human gastric carcinoma cells with bile acids results in activation of epidermal growth factor receptor (EGFR)-extracellular signal regulated kinase (ERK)1/2, which is also important for regulating cellular growth. Phosphoactivation of EGFR following treatment of cells with deoxycholate (DC) is ligand-dependent, since treatment of cells with heparin-binding EGF-like growth factor (HB-EGF) antisera or CM197 (a selective inhibitor of HB-EGF) markedly inhibited. Membrane-type bile acid receptor (M-BAR) BG37/TGR5 is a recently identified GPCR (G-protein-coupled receptor) for bile acids. Introduction of siRNAs that target M-BAR mRNA for degradation results in potent suppression of DC-induced phosphorylation of EGFR on tyrosine, as well as ERK1/2 activation, in AGS cells. Furthermore, pretreatment of cells with the metalloprotease inhibitor BiPS resulted in potent inhibition of DC-induced EGFR activation in AGS cells. Finally, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results lead us to conclude that bile acids transactivate EGFR through M-BAR-and ADAM/HB-EGF-dependent mechanisms in AGS cells. M-BAR, which may be involved in gastric carcinogenesis, could potentially serve as a target for cancer prevention.

胆汁酸与胃肠道的癌变有关，具有肿瘤促进剂的特性，两者都影响负责细胞增殖的细胞信号转导途径。多项研究的结果表明，丝裂原活化蛋白激酶的激活与胆汁酸的细胞效应有关。在本研究中，我们证明胆汁酸处理AGS人胃癌细胞会导致表皮生长因子受体(EGFR)-细胞外信号调节激酶(ERK)1/2的激活，这也是调节细胞生长的重要因素。用脱氧胆酸盐(DC)处理细胞后，EGFR的磷酸化激活是配体依赖的，因为用肝素结合的EGF样生长因子(HB-EGF)抗血清或CM197(HB-EGF的选择性抑制剂)处理细胞明显受到抑制。膜型胆汁酸受体(M-bar)BG37/TGR5是最近发现的一种胆汁酸G蛋白偶联受体。在AGS细胞中，引入针对M-bar mRNA降解的siRNAs可以有效地抑制DC诱导的EGFR对酪氨酸的磷酸化以及ERK1/2的激活。此外，金属蛋白酶抑制剂BIPS可有效抑制DC诱导的AGS细胞中EGFR的激活。最后，针对ADAM17转录本的siRNAs的引入抑制了DC诱导的EGFR和ERK1/2的激活。这些结果使我们得出结论，胆汁酸在AGS细胞中通过M-bar和ADAM/HB-EGF依赖的机制反式激活EGFR。M-bar可能参与胃癌的发生，有可能成为癌症预防的靶点。

项目成果

Autocrine Loop between Transforming Growth Factor-β1 and Interleukin-1β through Smad3- and ERK-dependent Pathways in Rat Pancreatic Stellate Cells.

大鼠胰腺星状细胞中转化生长因子-β1 和白介素-1β 通过 Smad3 和 ERK 依赖性途径之间的自分泌循环。

• 发表时间: 2006
• 期刊: Am J Physiol Cell Physiol. 290
• 作者: Aoki H;Ohnishi H;Hama K;Ishijima T;Satoh Y;Hanatsuka K;Ohashi A;Wada A;Miyata T;Kita H;Yamamoto H;Osawa H;Sato K;Tamada K;Yasuda H;Mashima H;Sugano K
• 通讯作者: Sugano K

Modified diagnostic criteria of drug-induced liver injury proposed by the international consensus meeting.

国际共识会议提出修订的药物性肝损伤诊断标准。

• 发表时间: 2005
• 期刊: Hepato-Gastroenterol. 52
• 作者: Iwasa M;Zeniya M;Kumagai T;Hisamochi A;Yasuda H;Nishiuchi M;Akisawa N;Mantani N;Watanabe M;Ito T;Nakamura A;Takikawa H;Adachi Y.
• 通讯作者: Adachi Y.

Regions in the G protein γ subunit important for interaction with receptors and effectors

• DOI: 10.1124/mol.105.018994
• 发表时间: 2006-03-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Myung, CS;Lim, WK;Garrison, JC
• 通讯作者: Garrison, JC

Acute necrotizing esophagitis: role of nonsteroidal anti-inflammatory drugs

• DOI: 10.1007/s00535-005-1741-6
• 发表时间: 2006-03-01
• 期刊: JOURNAL OF GASTROENTEROLOGY
• 影响因子: 6.3
• 作者: Yasuda, H;Yamada, M;Yoshiba, M
• 通讯作者: Yoshiba, M

Autocrine Loop between Transforming Growth Factor-β1 and Interleukin-1β through Smad3-and ERK-dependent Pathways in Rat Pancreatic Stellate Cells.

大鼠胰腺星状细胞中转化生长因子-β1 和白介素-1β 通过 Smad3 和 ERK 依赖性途径之间的自分泌循环。

• 发表时间: 2006
• 期刊: Am J Physiol Cell Physiol. 290
• 作者: Aoki H;Ohnishi H;Hama K;Ishijima T;Satoh Y;Hanatsuka K;Ohashi A;Wada A;Miyata T;Kita H;Yamamoto H;Osawa H;Sato K;Tamada K;Yasuda H;Mashima H;Sugano K.
• 通讯作者: Sugano K.