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首页> 外文学位 >Mechanisms of cellular immortalization in normal human oral keratinocytes.
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Mechanisms of cellular immortalization in normal human oral keratinocytes.

机译：正常人口腔角质形成细胞中细胞永生化的机制。

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摘要

The development of cancer is a multi-step process that occurs via accumulation of a series of discrete, irreversible, and complementary events. Among these events, the escape of cells from senescence is a critical step, since it could lead to immortalization and tumorigenic transformation of cells. To understand the in-depth mechanisms of cellular senescence and immortalization we investigated the role of Bmi-1, a polycomb group protein identified as c-myc cooperating oncogene in murine lymphomagenesis, in oral carcinogenesis and on the phenotypic changes of normal human oral keratinocytes (NHOK).;First, we determined the status of in situ Bmi-1 expression in human squamous cell carcinomas and human oral preneoplastic tissues using immunohistochemical staining. The level of Bmi-1 was almost negligible in normal tissues, but it was notably increased in preneoplastic oral lesions and cancer tissue, indicating that enhanced Bmi-1 expression is likely associated with oral carcinogenesis and the phenotypic changes of NHOK. Second, we found that an ectopic expression of Bmi-1 extended the lifespan of NHOK in vitro. Extension of life span by Bmi-1 was not associated with enhanced expression of hTERT (human telomerase reverse transcriptase) or repression of p53 and p16INK4A. We found that Bmi-1 interfered with the TGF-beta-mediated growth arrest response in NHOK by inhibiting phosphorylation of Smad2 and led to reduced expression of TGF-beta-specific cyclin-dependent kinase inhibitors such asp15INK4B and p57KIP2. However, Bmi-1 alone did not result in cellular immortalization of NHOK, which required additional factors, such as human papillomavirus type 16 (HPV-16) E6. HPV-16 E6 expression in NHOK overexpressing Bmi-1 led to immortalization by allowing enhanced expression of hTERT and activation of telomerase. hTERT activation during immortalization occurred by physical interaction of hsp90 protein onto hTERT promoter region, which was necessary for the enhanced hTERT expression in cells.;Together, our findings suggest that NHOK might convert to immortal cells when the cells lose several defensive mechanisms including TGF-beta-mediated growth arrest and the loss of telomerase activity, but not p 16INK4A , p53, or p21WAF1.
机译：癌症的发展是一个多步骤的过程，它通过一系列离散，不可逆和互补事件的积累而发生。在这些事件中，细胞从衰老中逃逸是至关重要的一步，因为它可能导致细胞永生化和致瘤转化。为了了解细胞衰老和永生化的深入机制，我们研究了Bmi-1（一种被鉴定为c-myc合作致癌基因的多梳子基团蛋白）在小鼠淋巴瘤发生，口腔癌变和正常人口腔角质形成细胞表型变化中的作用（首先，我们使用免疫组织化学染色确定了人类鳞状细胞癌和人类口腔癌前组织中原位Bmi-1表达的状态。在正常组织中，Bmi-1的水平几乎可以忽略不计，但在癌前口腔病变和癌组织中Bmi-1的水平显着增加，表明Bmi-1表达的增强可能与口腔癌变和NHOK的表型改变有关。其次，我们发现Bmi-1的异位表达延长了NHOK的寿命。 Bmi-1延长寿命与hTERT（人类端粒酶逆转录酶）的表达增强或p53和p16INK4A的抑制无关。我们发现Bmi-1通过抑制Smad2的磷酸化来干扰NHOK中TGF-β介导的生长停滞反应，并导致TGF-β特异性细胞周期蛋白依赖性激酶抑制剂（如p15INK4B和p57KIP2）的表达降低。但是，仅Bmi-1不会导致NHOK细胞永生化，这需要其他因素，例如16型人乳头瘤病毒（HPV-16）E6。过表达Bmi-1的NHOK中HPV-16 E6的表达通过增强hTERT的表达和激活端粒酶而导致永生。永生化过程中的hTERT激活是由于hsp90蛋白与hTERT启动子区域发生物理相互作用而发生的，这对于增强hTERT在细胞中的表达是必要的。在一起，我们的研究结果表明，当细胞失去包括TGF- β介导的生长停滞和端粒酶活性的丧失，但不是p 16INK4A，p53或p21WAF1。

著录项

  • 作者

    Kim, Reuben Han-Kyu.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Health Sciences Dentistry.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 170 p.
  • 总页数 170
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 口腔科学;肿瘤学;
  • 关键词

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