Identification Of Genes Involved In Tumorigenesis That Are Deregulated, With An Emphasis On Altered Dna Methylation.

Overview

Epigenetic modifications, including DNA methylation, cause heritable alterations in gene expression via mechanisms that do not affect the base sequence of DNA. Variations in levels of methylation (i.e. 5-methylcytosine) are responsible for transcriptional changes that occur during normal development, as well as disease states, including cancer. Tumorigenesis is a multistep process that is comprised of 3 experimentally-defined stages: initiation, promotion, and progression. Epigenetic mechanisms such as DNA ...
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Overview

Epigenetic modifications, including DNA methylation, cause heritable alterations in gene expression via mechanisms that do not affect the base sequence of DNA. Variations in levels of methylation (i.e. 5-methylcytosine) are responsible for transcriptional changes that occur during normal development, as well as disease states, including cancer. Tumorigenesis is a multistep process that is comprised of 3 experimentally-defined stages: initiation, promotion, and progression. Epigenetic mechanisms such as DNA methylation, plus mutations, can be key contributors to each phase. These changes facilitate the progressive clonal expansion of aberrant subpopulations that possess growth advantages, which ultimately results in the development of frank tumors. The overall goal of this dissertation research was to elucidate progressive changes, in expression and DNA methylation status, of genes which play key roles in liver tumorigenesis induced by the nongenotoxic hepatocarcinogen phenobarbital (PB), with an emphasis on their potential to affect signaling through critical pathways involved in the regulation of cell growth and differentiation. My hypothesis states that genes which are deregulated uniquely in liver tumor-susceptible, as compared to resistant mice, are among those that are mechanistically important for tumorigenesis. Two distinct model systems, representing a continuum of treatment, were utilized in combination to evaluate PB-elicited alterations that arose uniquely in the susceptible mice. Genes were identified that exhibited unique altered methylation and/or expression statuses in (1) B6C3F1 mice, as compared to the relatively resistant C57BL/6, at 2 and/or 4 weeks of PB treatment, and (2) precancerous liver and/or liver tumor tissue from constitutive active/androstane receptor (CAR) wildtype (WT) mice, as compared to liver tissue from PB-treated resistant CAR knockout (KO) mice. Notably, many of the genes are involved in pathways and processes that can control malignant growth (e.g., cell cycle, apoptosis, angiogenesis, invasion/metastasis, epithelial-mesenchymal cell transition, plus transforming growth factor-beta and Wnt signaling). The progressive nature of carcinogenesis is demonstrated by the observation that genes whose expression or methylation statuses were disrupted at 2 and/or 4 weeks remained deregulated in precancerous liver and/or liver tumor tissue. Unique expression changes of DNA methyltransferase (Dnmt) genes in tumor-prone B6C3F1 and CAR WT mice, plus the observation that they harbor CAR response elements (CAREs), suggest a potential direct link between PB and altered DNA methylation. CAREs within numerous additional genes whose expression and/or methylation statuses were altered uniquely, is evidence of the possible functions of CAR during tumor development. Significantly, candidate genes for "fingerprints" of early and late times of PB treatment, including tumors, are proposed. My dissertation research culminated in the identification of genes that, by virtue of their unique deregulation in tumor-prone, as compared to resistant mice, could contribute to tumorigenesis. Collectively, these data provide novel insight into a detailed picture of DNA methylation and gene expression changes that facilitate PB-induced hepatocarcinogenesis.
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Product Details

  • ISBN-13: 9781243626622
  • Publisher: BiblioLabsII
  • Publication date: 9/4/2011
  • Pages: 412
  • Product dimensions: 7.44 (w) x 9.69 (h) x 0.84 (d)

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