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首页> 外文学位 >The Aging Lung and Cancer: Evidence of Field Cancerization from Transcriptional Profiles of Normal Human and Mouse Lung Tissues.
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The Aging Lung and Cancer: Evidence of Field Cancerization from Transcriptional Profiles of Normal Human and Mouse Lung Tissues.

机译：衰老的肺癌和癌症：从正常人和小鼠肺组织的转录谱中发现田野癌化的证据。

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摘要

The effect of increased age on gene expression has not previously been evaluated in lung tissues. Cancer incidence increases with age, and lung cancer in particular has been found to have an incidence that peaks in the later decades of life. Based on previously published studies of aging effects in human muscle, kidney and retinal tissues, significant transcriptional changes are anticipated in both mouse and human aged lung tissues that may predispose to the development of cancer.;In mouse tissues, induced metastatic disease was found to be associated with reduced overall survival in older mice. The pattern of pulmonary metastases was more diffuse as compared to younger mice. Age-related transcriptional changes in the lung of extremely old hybrid mice were related to altered effectors of the immune system, regulators of angiogenesis and elements of DNA repair mechanisms, likely explaining the molecular basis behind the altered patterns of pulmonary metastasis observed in the extremely old mice.;In human tissues, eighty-two genes were differentially expressed in a statistically significantly manner. Most genes were downregulated in aged lung tissue and included collagen isoforms and proteins responsible for extracellular matrix synthesis and turnover. A single upregulated transcript was a MYC binding protein. Selected transcripts were validated by PCR and histochemical staining.;This is the first examination of lung metastases and the molecular biology of lung tissues at the extremes of age. Alterations to gene expression profiles was observed in both mouse and human lung tissues, and supports the concept of a field defect in normal lung tissues that develops with increased age.;We examined lung aging between young and old mice (6 vs. 30 months), using a hybrid mouse model (CB6F1) and an experimental colorectal metastasis model (CT26 cells). We also recruited young (30 years) and aged (>60 years) human patients. Microarray analysis of mouse lung tissues using MOE430v2 and human lung tissues suing HG U133 2.0+ Affymetrix arrays was performed using total lung RNA, after which expression values were computed from .CEL files by applying RMA normalization within sets of replicate samples. Statistical testing was performed using the significance analysis of microarrays algorithm. Statistically significant transcripts were validated by histochemical staining and quantitative polymerase chain reactions (PCR).
机译：以前尚未在肺组织中评估年龄增加对基因表达的影响。癌症的发病率随年龄增长而增加，特别是肺癌的发病率在生命的后几十年达到顶峰。根据先前发表的有关人类肌肉，肾脏和视网膜组织衰老影响的研究，预计小鼠和人类老年肺组织都有明显的转录变化，这可能会导致癌症的发展。在小鼠组织中，发现诱发转移性疾病与衰老小鼠的总生存期降低有关。与年轻小鼠相比，肺转移的模式更为弥散。极老的杂种小鼠的肺中与年龄相关的转录变化与免疫系统的效应子，血管生成的调节剂和DNA修复机制的要素有关，这可能解释了在极老的小鼠中观察到的肺转移模式改变的分子基础。在人体组织中，有82个基因以统计学上显着的方式差异表达。大多数基因在老年肺组织中被下调，其中包括负责细胞外基质合成和更新的胶原同工型和蛋白质。单个上调的转录物是MYC结合蛋白。通过PCR和组织化学染色对选定的转录本进行验证。；这是首次检测极端年龄的肺转移和肺组织的分子生物学。在小鼠和人的肺组织中均观察到基因表达谱的改变，并支持了随着年龄增长而在正常肺组织中出现野外缺损的概念。我们研究了年轻小鼠和老年小鼠之间的肺衰老（6 vs. 30个月） ，使用混合小鼠模型（CB6F1）和实验性结肠直肠转移模型（CT26细胞）。我们还招募了年轻（<30岁）和年龄（> 60岁）人类患者。使用总肺RNA对使用MOE430v2的小鼠肺组织和使用HG U133 2.0+ Affymetrix阵列的人肺组织进行微阵列分析，然后通过在重复样品组中应用RMA归一化从.CEL文件计算表达值。使用微阵列算法的显着性分析进行统计学检验。统计显着的成绩单已通过组织化学染色和定量聚合酶链反应（PCR）进行了验证。

著录项

  • 作者

    Villeneuve, Patrick James.;

  • 作者单位

    University of Ottawa (Canada).;

  • 授予单位 University of Ottawa (Canada).;
  • 学科 Chemistry Biochemistry.;Health Sciences Aging.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 146 p.
  • 总页数 146
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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