THE ROLE OF LIN28B IN WILMS TUMOR

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、葡萄糖代谢控制和肿瘤发生。它调节最古老和高度保守的microRNA （miRNA）家族之一let-7，通过阻止它们加工成成熟的miRNA。LIN28B的激活已经在越来越多的各种癌症中得到证实，特别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，在肾形成过程中，在肾脏中过度表达LIN28B的小鼠会发展成一种恶性肿瘤，这种恶性肿瘤与儿童时期最常见的肾脏肿瘤威尔姆斯瘤非常相似。肾母细胞瘤起源于多能性胚胎肾前体细胞，并与持续存在的胚胎肾组织有关。先前的研究表明，WT1肿瘤抑制因子的缺失会导致Wilms肿瘤，但WT1缺乏占所有肿瘤的不到三分之一。我们的研究表明LIN28B是一种新的途径，在这个应用中，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特异性途径或靶点的发现将为我们对LIN28B肿瘤发生的机制理解增加相当深度，并可能对确定治疗方法具有重要意义。人们很容易认识到LIN28B在肿瘤发生中的重要性，该领域的主要焦点之一是了解人类癌症中LIN28B上调的机制。以往的研究主要集中在LIN28B基因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，有几组报告了Wilms肿瘤的染色体易位，涉及LIN28B所在的染色体带。当分析两个携带易位的Wilms肿瘤病例时，与正常肾脏相比，肿瘤样本中LIN28B的表达明显增加。因此，我假设在某些情况下，LIN28B可能被染色体易位激活以驱动肿瘤发生。对易位的研究可能会提供一种内源性的、基于突变的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的诊断和治疗靶点。

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.