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首页> 外文期刊>Journal of Cellular Physiology >RECK Inhibits Stemness Gene Expression and Tumorigenicity of Gastric Cancer Cells by Suppressing ADAM-Mediated Notch1 Activation
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RECK Inhibits Stemness Gene Expression and Tumorigenicity of Gastric Cancer Cells by Suppressing ADAM-Mediated Notch1 Activation

机译：介意具备干细胞抑制基因表达胃癌细胞的致瘤性抑制ADAM-Mediated Notch1激活

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摘要

The Reversion-inducing Cysteine-rich Protein with Kazal Motifs (RECK) gene encodes a membrane-anchored glycoprotein that exhibits strong inhibitory activity against various matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase 10 (ADAM10). RECK functions as a tumor suppressor by inhibiting migration, invasion, and angiogenesis. However, whether RECK can modulate the stem-like phenotypes of cancer cells is not known. In this study, we demonstrate that RECK is down-regulated in gastric cancer cells and is further reduced in CD133-positive cancer stem-like cells. Ectopic expression of RECK induces down-regulation of the expression of stemness genes including Sox2, Oct4, and Nanog and the cancer stem cell marker CD133. Treatment of DAPT (a γ-secretase inhibitor) or TAPI-2 (a hydroxamate-based inhibitor of MMPs, tumor necrosis factor α converting enzyme and ADAM17) reduces Notch1 shedding and activation which results in attenuation of stemness genes and CD133. Our data show that ADAM10 and ADAM17 are co-pulled down by RECK suggesting a physical interaction between RECK and ADAMs on cell surface. In addition, RECK suppresses sphere formation and sphere size of CD133-positive gastric cancer cells. Overexpression of Notch intracellular domain (NICD) or ADAM17 effectively reverse the inhibitory effect of RECK in CD133-positive cells. More importantly, RECK reduces tumorigenic activity of CD133-positive cells in vivo. Conversely, knockdown of RECK in non-tumorigenic GI2 cells increases stemness and CD133 expression and sphere forming ability. Collectively, these results indicate that RECK represses stemness gene expression and stem-like properties by inhibiting ADAM-mediated Notch1 shedding and activation.
机译：的Reversion-inducing Cysteine-rich蛋白质Kazal Motifs (RECK基因encodes) amembrane-anchored糖蛋白,展品强烈抑制活动对各种矩阵金属蛋白酶()和disintegrin金属蛋白酶10 (ADAM10)。一个肿瘤抑制通过抑制迁移,入侵和血管生成。可以调节癌症干细胞表型的细胞是未知的。抑制在胃癌有关系细胞和CD133-positive进一步降低癌症干细胞样细胞。介意诱发的表达下调具备干细胞基因包括Sox2 Oct4、Nanog和癌症干细胞标志物CD133。榫眼(γ分泌酶抑制剂)或TAPI-2 (ahydroxamate-based基质金属蛋白酶抑制剂,肿瘤坏死因子α转换酶和ADAM17)减少Notch1脱落和激活结果在具备干细胞基因和衰减CD133。co-pulled顾虑建议物理介意和亚当斯在细胞之间的相互作用表面。形成和球体CD133-positive的大小胃癌细胞。胞内域研究所或ADAM17有效反向顾虑的抑制作用CD133-positive细胞。减少CD133-positive肿瘤发生的活动细胞体内。非致瘤性GI2具备干细胞和细胞增加CD133表达和球面成形能力。总的来说,这些结果表明,顾虑压制具备干细胞基因表达和干细胞属性通过抑制ADAM-mediated Notch1流和激活。

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  • 来源
    《Journal of Cellular Physiology》 |2014年第2期|191-201|共11页
  • 作者

    HongK.-J.; WuD.-C.; ChengK.-H.ChenL.-T.HungW.-C.;

  • 作者单位

    Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan;

    Division of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical;

    Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical UniversityInstitute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, National;

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  • 正文语种 英语
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  • 关键词

    cancer cell; ADAM17 gene; TumorigenicityAC133 Antigen;

    机译：癌细胞;ADAM17基因;TumorigenicityAC133抗原;

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