THE ROLE OF LIN28B IN WILMS TUMOR

LIN28B 在肾母细胞瘤中的作用

• 批准号: 8970550
• 负责人: Alena Yermalovich
• 金额: $ 3.54万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-02 至 2017-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970550
• 关键词: Accounting; Case Study; Childhood Renal Neoplasm; Chromosomal Rearrangement; Chromosomal translocation; Development; Diagnosis; Embryo; Epigenetic Process; Family; Frequencies; Gene Activation; Gene Fusion; Genes; Genetic; Genomics; Goals; Human; In Vitro; Kidney; Laboratories; Lead; Light; Malignant Neoplasms; Malignant childhood renal neoplasm; Maps; MicroRNAs; Molecular; Mus; Mutation; Nephroblastoma; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Process; Proteins; RNA-Binding Proteins; Renal Tissue; Role; Sampling; Stem cells; Sum; Therapeutic; Tumor Suppressor Proteins; Up-Regulation; WT1 gene; base; fusion gene; glucose metabolism; in vivo; insight; mouse model; nephrogenesis; novel; organ growth; outcome forecast; overexpression; precursor cell; public health relevance; stem cell biology; tumor; tumorigenesis

DESCRIPTION (provided by applicant): LIN28B is a highly conserved RNA-binding protein that is involved in development, stem cell biology, control of glucose metabolism, and tumorigenesis. It regulates one of the most ancient and highly conserved microRNA (miRNA) families, let-7, by blocking their processing into mature miRNAs. Activation of LIN28B has been documented in a growing list of various cancers, especially those that are highly aggressive and poorly differentiated. Our laboratory recently discovered that mice overexpressing LIN28B in the kidneys during nephrogenesis develop a malignancy highly reminiscent of the most common renal neoplasm of childhood, Wilms' tumor. Wilms' tumor arises from pluripotent embryonic kidney precursor cells and is associated with persistent embryonic renal tissue. Prior studies have implicated that loss of the WT1 tumor suppressor leads to Wilms tumors, but WT1 deficiency accounts for less than a third of all tumors. Our studies have implicated LIN28B as a novel pathway, and in this application I propose to study LIN28B in both normal kidney development and tumorigenesis. It is my hope that discovery of Wilms' specific pathways or targets would add considerable depth to our mechanistic understanding of LIN28B tumorigenesis and may be important for defining therapeutic approaches. The importance of LIN28B in tumorigenesis is readily appreciated and one of major focuses of the field has been to understand the mechanisms that underlie LIN28B upregulation in human cancers. Previous studies concentrated on genomic amplification and aberrant hypomethylation of LIN28B loci as possible mechanisms of activation of the gene in tumors. It's been shown that while these genetic and epigenetic alterations indeed occur in a small subset of cancers, they are unlikely to be dominant mechanisms of LIN28B activation. Notably, several groups reported cases of Wilms' tumor with a chromosomal translocation involving the band in which LIN28B is located. When two Wilms' tumor cases carrying translocations were analyzed, they showed notably increased expression of LIN28B in the tumor samples compared with normal kidneys. Therefore, I hypothesize that LIN28B may be activated by chromosomal translocation to drive oncogenesis in some case. Study of the translocation might provide an endogenous, mutation-based mechanism of LIN28B activation, as it occurs in human patients and help to expose new potential targets for diagnosis and therapy.

描述（由申请人提供）：LIN28B是一种高度保守的RNA结合蛋白，参与发育、干细胞生物学、葡萄糖代谢的控制和肿瘤发生。它通过阻止其加工成成熟 miRNA 来调节最古老且高度保守的 microRNA (miRNA) 家族之一 let-7。 LIN28B 的激活已在越来越多的各种癌症中得到记录，尤其是那些高度侵袭性和低分化的癌症。我们的实验室最近发现，在肾发生过程中肾脏中过度表达 LIN28B 的小鼠会发展出一种恶性肿瘤，这与儿童期最常见的肾肿瘤——肾母细胞瘤非常相似。肾母细胞瘤起源于多能胚胎肾前体细胞，并与持续性胚胎肾组织相关。先前的研究表明，WT1 肿瘤抑制因子的缺失会导致肾母细胞瘤，但 WT1 缺陷仅占所有肿瘤的三分之一。我们的研究表明 LIN28B 是一种新途径，在本申请中，我建议研究 LIN28B 在正常肾脏发育和肿瘤发生中的作用。我希望 Wilms 的特定途径或靶点的发现能够极大地加深我们对 LIN28B 肿瘤发生机制的理解，并且对于确定治疗方法可能很重要。 LIN28B 在肿瘤发生中的重要性显而易见，该领域的主要焦点之一是了解人类癌症中 LIN28B 上调的机制。先前的研究集中于 LIN28B 位点的基因组扩增和异常低甲基化，作为肿瘤中该基因激活的可能机制。研究表明，虽然这些遗传和表观遗传改变确实发生在一小部分癌症中，但它们不太可能是 LIN28B 激活的主要机制。值得注意的是，几个小组报告了肾母细胞瘤病例，其染色体易位涉及 LIN28B 所在条带。当对两例携带易位的肾母细胞瘤病例进​​行分析时，发现与正常肾脏相比，肿瘤样本中 LIN28B 的表达显着增加。因此，我推测 LIN28B 可能通过染色体易位被激活，在某些情况下驱动肿瘤发生。对易位的研究可能会提供一种基于突变的内源性 LIN28B 激活机制，因为它发生在人类患者中，并有助于揭示新的潜在诊断和治疗靶点。