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首页> 外文学位 >Loss of insulin-like growth factor II receptor in tumorigenic murine cells: Effects on growth and invasion.
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Loss of insulin-like growth factor II receptor in tumorigenic murine cells: Effects on growth and invasion.

机译：致瘤鼠细胞中胰岛素样生长因子II受体的丢失：对生长和侵袭的影响。

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摘要

A variety of human cancers including breast, liver, colorectal, lung, and prostate cancers have loss of heterozygosity (LOH) of the igf2r gene locus on chromosome 6q26-27. These data suggest that the IGF-IIR may be a tumor suppressor. Our findings demonstrate that loss of expression of the IGF-IIR in both murine L and MMSV fibroblasts promotes growth. In murine L cells, loss of IGF-IIR sustains high levels of IGF-II mitogen, which binds and activates both the IGF-I and insulin receptors to increase the duration and extent of the intracellular growth signal, phospho-IRS-1. IGF-IIR deficient MMSV clones grow more rapidly than MMSV clones engineered to over-express the IGF-IIR under serum-free conditions when cells are initially primed with 10% serum. IGF-II cannot substitute for serum during the initial priming step and TGF-β does not inhibit growth of IGF-IIR deficient MMSV cells to levels of IGF-IIR positive cells. Thus, the results suggest factors other than IGF-II or TGF-β either in serum or produced by the cells mediate the growth of IGF-IIR deficient MMSV cells. To evaluate the invasive potential of these murine cells, an in vitro invasion assay was performed. Murine L cells rapidly invade through Matrigel. Interestingly, loss of expression of the IGF-IIR in L cells decreases their ability to degrade Matrigel compared to L cells that over-express the IGF-IIR. Conversely, MMSV cells are poor invaders of Matrigel and loss of IGF-IIR expression in these cells has little effect on their ability to degrade to Matrigel. The invasiveness of IGF-IIR positive L cells is inhibited by 30% in the presence of CA-O74Me, an intracellular inhibitor of cathepsin B. These results suggest that an increase in levels of intracellular active lysosomal enzymes such as cathepsin B is partly responsible for the increase in invasion of tumorigenic murine L cells that express the IGF-IIR.{09}These results suggest that loss of IGF-IIR expression can stimulate the growth of tumor cells but could decrease their ability to degrade extracellular matrix for some cell types.
机译：包括乳腺癌，肝癌，结肠直肠癌，肺癌和前列腺癌在内的多种人类癌症都丧失了6q26-27号染色体上igf2r基因位点的杂合性（LOH）。这些数据表明IGF-IIR可能是肿瘤抑制物。我们的发现表明，鼠L和MMSV成纤维细胞中IGF-IIR表达的缺失促进了生长。在鼠L细胞中，IGF-IIR的丧失维持了高水平的IGF-II促分裂原，它结合并激活了IGF-I和胰岛素受体，从而增加了细胞内生长信号磷酸-IRS-1的持续时间和范围。 IGF-IIR缺陷型MMSV克隆的生长速度比MMSV克隆快得多，而该MMSV克隆经过工程设计可在无血清条件下过表达IGF-IIR（最初用10％血清灌注细胞）。在初始启动步骤中，IGF-II不能替代血清，并且TGF-β不会将IGF-IIR缺陷型MMSV细胞的生长抑制到IGF-IIR阳性细胞的水平。因此，结果提示血清中或由细胞产生的除IGF-II或TGF-β以外的因子介导IGF-IIR缺陷型MMSV细胞的生长。为了评估这些鼠细胞的侵袭潜能，进行了体外侵袭试验。鼠L细胞通过基质胶快速侵袭。有趣的是，与过表达IGF-IIR的L细胞相比，L细胞中IGF-IIR的表达丧失降低了其降解基质胶的能力。相反，MMSV细胞对基质胶的侵袭性较弱，这些细胞中IGF-IIR表达的丧失对其降解为基质胶的能力几乎没有影响。在组织蛋白酶B的细胞内抑制剂CA-O74Me的存在下，IGF-IIR阳性L细胞的侵袭性受到30％的抑制。这些结果表明，细胞内活性溶酶体酶（例如组织蛋白酶B）水平的升高是其中的部分原因{09}这些结果表明，IGF-IIR表达的丧失可刺激肿瘤细胞的生长，但可能会降低某些细胞类型降解细胞外基质的能力。

著录项

  • 作者

    Osipo, Clodia.;

  • 作者单位

    Loyola University of Chicago.;

  • 授予单位 Loyola University of Chicago.;
  • 学科 Chemistry Biochemistry.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 128 p.
  • 总页数 128
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;肿瘤学;
  • 关键词

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