Reactivation of embryonic growth programs in liver cancer

描述（由申请人提供）：异慢性基因编码的产物在组织中随时间表达变化，暂时调节发育变化和器官生长bbb。例如，许多异慢性基因在胎儿中表达，但在成人组织中不表达，因此它们促进胎儿组织的快速生长，并在出生后被关闭。癌症可以在成人组织中重新激活这些异慢性基因，使肿瘤增殖成为可能。这些基因在正常和恶性生物学中的作用尚不清楚，因为不能在体外研究发育时间，而且很少有这些基因在体内系统地研究过。Lin28是一种异慢性rna结合蛋白，以其抑制let-7 microRNAs （miRNAs）的生物发生能力而闻名，let-7 microRNAs是一种古老的肿瘤抑制因子，可抑制癌基因的翻译，从而损害细胞生长[3,4]。在过去的4年里，我通过使用小鼠模型揭示了异慢性基因的重要作用，这些模型允许暂时特定的Lin28和let-7的增加或减少。我发现适度增加Lin28a的表达会显著增加小鼠的生长、身高和进入青春期的时间，这表明它在从蠕虫到小鼠的发育时间中起着保守的作用。接下来，我们发现Lin28和let-7是哺乳动物糖代谢的调节因子，暗示异慢性基因参与了糖尿病的发病机制。最近，我们发现Lin28a的成体再激活促进了类似于胚胎组织[7]的再生能力。Lin28暂时整合胚胎代谢、细胞增殖和组织生长的能力提高了它通过这些机制促进成人肿瘤发生的可能性。我们将重点研究肝脏肿瘤的小鼠模型，因为LIN28B在高达40%的儿童和成人肝癌中过表达，并且因为肝癌是一个主要的全球问题，治疗方案有限[8,9]。在前期研究中，我们发现LIN28B过表达足以诱导成年小鼠肝癌。我们还发现，MYC过表达会产生高Lin28b和低let-7表达的肝脏肿瘤，我们的数据表明，这些肝癌的发展需要Lin28b。在AIM 1中，我们将测试持续的Lin28b表达是否需要肿瘤维持或生长，然后我们将评估Lin28b丢失的代谢后果。在AIM 2中，我们将确定let-7 mirna的抑制是否对肝脏肿瘤的发展是必要的，我们将评估可能负责的代谢和再生机制。我们还发现Igf2 mRNA结合蛋白1和3 （Imp1和Imp3）是已知的let-7靶点和mRNA翻译的调节因子，在LIN28B过表达的肿瘤中被有效诱导。在AIM3中，我们将测试Imp1和Imp3的表达对于肝脏肿瘤的生长是否必要或充分，Imp1/3的变化是否介导Lin28对代谢的影响。这一建议有可能剖析正常调节生长、代谢和再生的异慢性途径在癌症中的作用。

DESCRIPTION (provided by applicant): Heterochronic genes encode products whose expression changes over time in tissues, temporally regulating developmental changes and organ growth [1]. For example, many heterochronic genes are expressed in fetal, but not adult tissues such that they promote the rapid growth of fetal tissues and are shut off postnatally. Cancers can reactivate these heterochronic genes in adult tissues to enable neoplastic proliferation [2]. The role of these genes in normal and malignant biology is not well understood because developmental timing cannot be studied in vitro, and few of these genes have been systematically investigated in vivo. Lin28 is a heterochronic RNA-binding protein known for its ability to inhibit the biogenesis of let-7 microRNAs (miRNAs), ancient tumor suppressors that suppress the translation of oncogenes to impair cellular growth [3, 4]. Over the last 4 years I have uncovered important roles for heterochronic genes by using murine models that allow temporally specific gain or loss of Lin28 and let-7. I found that modestly increased expression of Lin28a substantially increased mouse growth, height, and time to puberty, demonstrating a conserved role in developmental timing from worms to mice [5]. Next, we showed that Lin28 and let-7 are regulators of mammalian glucose metabolism, implicating heterochronic genes in the pathogenesis of diabetes [6]. More recently, we showed that adult reactivation of Lin28a promotes regeneration capabilities reminiscent of embryonic tissue [7]. Lin28's ability to temporally integrate embryonic metabolism, cell proliferation, and tissue growth raises the possibility that it also promotes adult tumorigenesis through these mechanisms. We will focus on mouse models of liver tumors because LIN28B is overexpressed in up to 40% of pediatric and adult liver cancers, and because liver cancer is a major global problem with limited treatment options [8, 9]. In preliminary studies, we find that LIN28B overexpression is sufficient to induce liver cancer in adult mice. We have also found that MYC overexpression produces liver tumors with high Lin28b and low let-7 expression, and our data suggest that Lin28b is required for the development of these liver cancers. In AIM 1, we will test whether ongoing Lin28b expression is required for tumor maintenance or growth, then we will assess the metabolic consequences of Lin28b loss. In AIM 2, we will determine if the suppression of let-7 miRNAs is necessary for the development of liver tumors, and we will assess the metabolic and regenerative mechanisms that might be responsible. We have also shown that Igf2 mRNA-binding proteins 1 and 3 (Imp1 and Imp3), which are known let-7 targets and regulators of mRNA translation, are potently induced in LIN28B overexpressing tumors. In AIM3, we will test whether Imp1 and Imp3 expression are necessary or sufficient for the growth of liver tumors and whether changes in Imp1/3 mediate effects of Lin28 on metabolism. This proposal has the potential to dissect the role in cancer of a heterochronic pathway that normally regulates growth, metabolism, and regeneration.