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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer
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Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

机译:凋亡信号调节激酶1和细胞周期蛋白D1组成一个正反馈回路,有助于胃癌肿瘤的生长

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摘要

Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer.
机译:丝裂原激活的蛋白激酶(MAPK)通路调节多种细胞功能,并在许多类型的人类癌症中高度活跃。凋亡信号调节激酶1(ASK1)是上游MAPK,参与细胞凋亡,炎症和癌变。这项研究调查了ASK1在胃癌发展中的作用。在人类胃癌标本中,我们观察到与非肿瘤上皮相比,ASK1表达增加。使用化学诱导的鼠胃肿瘤发生模型,我们观察到了肿瘤ASK1表达的增加,并且与野生型(WT)小鼠相比,ASK1敲除小鼠的肿瘤更少且更小。 ASK1 siRNA通过在细胞周期的G1期中积累细胞来抑制细胞增殖,并降低胃癌细胞中cyclin D1的表达,而这些作用在其他癌细胞中并不常见。 ASK1过表达通过AP-1激活诱导细胞周期蛋白D1的转录,而ASK1水平则通过Rb-E2F途径受到细胞周期蛋白D1的调控。外源性ASK1诱导细胞周期蛋白D1表达,然后内源性ASK1表达升高。这些结果表明在胃癌的发展中ASK1的自调节机制。针对这一正反馈回路,ASK1可能为晚期胃癌的治疗提供潜在的治疗靶标。

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  • 作者单位

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo 100-0005, Japan;

    Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo 100-0005, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan;

    Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo 100-0005, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan;

    Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan,Department of Gastroenterology, Yokohama City University, Yokohama 236-0004, Japan;

    Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    JNK; c-Jun;

    机译:J-K;c-jun;

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