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Cancer Beyond the Coding Frontier: miRNAs, piRNAs, and the Epigenome in Human Oncogenesis.

机译：超越编码前沿的癌症：miRNA，piRNA和人类肿瘤发生中的表观基因组。

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摘要

The advent of small noncoding RNAs as important modulators of cancer susceptibility and progression has gained widespread recognition in recent years. This understanding was precipitated by the 1993 discovery of a 22--nucleotide RNA in C. elegant capable of translational repression but was itself never translated into protein. Since the unveiling of this first microRNA (miRNA), over 1,000 additional members of the miRNA superfamily have been uncovered in humans, together accounting for the regulation of an estimated 60% of the human genome. The near functional ubiquity of miRNAs has in turn provided the catalyst for a considerable number of molecular and epidemiological undertakings to elucidate the role of miRNAs in human cancers, leading to an enhanced understanding of miRNA function in human carcinogenesis. Indeed, the role of miRNAs in the oncogenic process has, in a relatively short period of time, evolved from being novel to canon, w ith implications in a wide spectrum of cancer types.;In contrast to the voluminous body of experimental and observational evidence that underpin the miRNA-cancer connection, knowledge of PIWI-interacting RNAs (piRNAs) in the carcinogenic process remains in its infancy. Although purportedly existing in over 20,000 unique species in the human genome, piRNAs enjoy few of the epistemiological advantages that allow miRNAs to be so readily studied in cancer. Elements of the biogenic process of piRNAs remain unelucidated, including the mechanism of transcription and the structure of the primary transcript, and we are only now starting to gain an appreciation of the potentially vast array of functions associated with the piRNA regulatory domain. Although it was believed that the primary role of piRNAs is to silence active transposable elements in the germ line and thereby guard the genome against transposon-induced insertional mutations, mounting evidence now point towards an active role for piRNAs in somatic gene regulation through sequencespecific histone modification and DNA methylation. Despite the broad implications this development holds for the study of piRNAs in cancer, current research of the PIWI/piRNA axis in human cancers is largely restricted to expression profiling of PIWI proteins and a narrow selection of individual piRNAs.;In this thesis, we use functional genetics to explicate the molecular behavior that underlies observed genetic associations between two small non coding RNAs and their respective cancer types. Chapter 1 details the results of our efforts to elucidate the functional link between a single nucleotide polymorphism (SNP) within the miR-61S precursor sequenceand its association with follicular non-Hodgkins lymphoma. Our findings reveal that the presence of the variant allele may negatively impact the production of mature effector miR--618 by interfering with the post-transcriptional miRNA biogenic process, in turn leading to the dysrcgulation of lymphoma-relevant miR-618 targets. In Chapter 2, we demonstrate the ability of certain piRNAs to affect - potentially by binding to DNA in a sequence-specific manner the DNA methylation of protein-coding genes in somatic cancer cell lines. This finding helps to establish a possible mechanism by which piRNAs may be able to alter one s susceptibility to cancer development, namely through piRNA-mediated DNA methylation of oncogenes and tumor suppressors. Lastly, in Chapter 3, we attem pt to reconcile an association between a SNP in piR-021285 and breast cancer with gene-specific DNA methylation differences found between wild type and variant piR-021285 mimic-transfected breast cancer cells. Our findings reveal that predominance of the variant allele may be associated with attenuated methylation and enhanced expression of the cell motility-related ARHGAPI1A gene, which may confer a hyper-invasive phenotype on breast tumor cells. Together, these findings help characterize a little studied miRNA in the lymphomagenic process by capitalizing upon a clearly defined biogenic process and mechanism of action, as well as reveal possible mechanisms through which a piRNA may able to alter breast cancer susceptibility and disease progression.
机译：近年来，小的非编码RNA作为癌症易感性和进展的重要调节剂的出现已获得广泛认可。这种理解是由1993年在C. Elegant中发现22个核苷酸的RNA引起的，该RNA具有翻译抑制能力，但其自身从未翻译成蛋白质。自从第一个microRNA（miRNA）问世以来，已经在人类中发现了超过1,000个miRNA超家族成员，共同构成了估计60％的人类基因组的调控。 miRNA的近乎功能性反过来又为许多分子和流行病学研究提供了催化剂，以阐明miRNA在人类癌症中的作用，从而导致人们对miRNA在人类致癌作用中的功能有了更深入的了解。实际上，miRNA在致癌过程中的作用已在相对较短的时间内从新颖发展为经典，这对多种癌症类型都有影响。;与大量的实验和观察证据相反作为miRNA-癌症联系基础的基础，在致癌过程中对PIWI相互作用RNA（piRNA）的了解仍处于起步阶段。尽管据称存在于人类基因组中的20,000多个独特物种中，但piRNA几乎没有表观学上的优势，这些优势使得miRNA易于在癌症中进行研究。尚不清楚piRNA的生物形成过程的要素，包括转录机制和一级转录本的结构，而且我们现在才开始认识到与piRNA调节域相关的潜在功能。尽管人们认为piRNA的主要作用是沉默种系中的活性转座因子，从而保护基因组免受转座子诱导的插入突变的影响，但现在越来越多的证据表明piRNA在序列特异性组蛋白修饰中在体细胞基因调控中发挥了积极作用。和DNA甲基化。尽管此进展对癌症中piRNA的研究具有广泛意义，但目前人类癌症中PIWI / piRNA轴的研究在很大程度上限于PIWI蛋白的表达谱分析和单个piRNA的选择范围狭窄。功能遗传学来阐明分子行为，这些分子行为是观察到的两个小的非编码RNA及其各自癌症类型之间遗传关联的基础。第1章详细介绍了我们为阐明miR-61S前体序列中的单核苷酸多态性（SNP）及其与滤泡性非霍奇金淋巴瘤之间的联系而做出的努力的结果。我们的发现表明，变异等位基因的存在可能会干扰转录后miRNA的生物生成过程，从而对成熟的效应器m​​iR-618的产生产生负面影响，进而导致与淋巴瘤相关的miR-618靶的失调。在第2章中，我们证明了某些piRNA的能力-可能通过以序列特异性方式与DNA结合来影响体癌细胞系中蛋白质编码基因的DNA甲基化。这一发现有助于建立一种可能的机制，使piRNA能够改变一个人对癌症发展的敏感性，即通过piRNA介导的癌基因和抑癌基因的DNA甲基化。最后，在第3章中，我们试图调和piR-021285中的SNP与乳腺癌之间的联系，以及野生型和变体piR-021285模拟转染的乳腺癌细胞之间发现的基因特异性DNA甲基化差异。我们的研究结果表明，变异等位基因的优势可能与甲基化减弱和细胞运动相关的ARHGAPI1A基因表达增强有关，这可能赋予乳腺肿瘤细胞超侵袭性表型。总之，这些发现通过利用明确定义的生物过程和作用机制，有助于在淋巴瘤发生过程中研究miRNA的特征，以及揭示piRNA可能通过这些机制改变乳腺癌易感性和疾病进展的机制。

著录项

  • 作者

    Fu, Alan.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Health Sciences Public Health.;Health Sciences Oncology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 166 p.
  • 总页数 166
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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