Identification and characterization of long noncoding RNAs in human melanomas

描述（由申请人提供）：长链非编码RNA（lncRNA）以发育和疾病调节的方式转录和表达，其在基因组中的功能是一个非常令人感兴趣的来源。该提案的主要重点是鉴定和表征转移性黑色素瘤特异性lncRNA，并进行机制研究以证明其与人类黑色素瘤的疾病相关性。我们对lncRNA对黑色素瘤的作用的兴趣源于我们最近的证明（Khaitan等人，Cancer Research 2011）的siRNA介导的黑色素瘤上调的长非编码RNA的敲低导致细胞生长、运动性和分化的缺陷，并诱导黑色素瘤细胞系的凋亡，表明长非编码RNA在黑色素瘤发展中的作用。最近，我们已经确定了一组差异表达的lncRNA在远处转移性黑色素瘤患者的样品相比，正常皮肤。我们坚信，这些信息有助于了解黑色素瘤转移，并开发针对这种癌症的诊断和治疗工具。在本申请中，我们提出了实验，以扩大我们的初步分析lncRNA的表达，以更大的患者群体，并确认我们的初步数据的统计学意义。基于我们的初步观察，我们假设差异表达的lncRNA是检测人类黑素瘤的有用生物标志物。我们提出以下具体目标来检验我们的中心假设。具体目标1：检验以下假设： 差异表达的黑色素瘤特异性lncRNA是用于人类黑色素瘤检测的有用生物标志物。具体目的2：鉴定黑色素瘤上调lncRNA AK023647的分子功能。这项研究的主要影响是首次证明lncRNA参与黑色素瘤的发展，超越了蛋白质编码基因的界限。这项拟议的研究有可能对我们对黑色素瘤发展的理解产生重大影响。 公共卫生相关性：黑色素瘤是一种皮肤癌，当它转移到其他器官时往往是致命的。我们建议确定长的非编码RNA为基础的分子标记，黑色素瘤的早期检测在人类。

DESCRIPTION (provided by applicant): Long non-coding RNAs (lncRNAs) are transcribed and expressed in a developmentally and disease-regulated manner and their function in the genome is a source of great interest. The primary focus of this proposal is to identify and characterize metastatic melanoma specific lncRNAs and conduct mechanistic studies to demonstrate their disease relevance to human melanomas. Our interest in the role of lncRNA to melanoma arises from our recent demonstration (Khaitan et al., Cancer Research 2011) of siRNA-mediated knock-down of a melanoma upregulated long noncoding RNA causes defects in cell growth, motility and differentiation, and induces apoptosis of melanoma cells lines, suggesting a role for long noncoding RNAs in melanoma development. Recently, we have identified a group of differentially expressed lncRNAs in distant metastatic melanoma patients' samples compared to normal skin. We strongly believe that this information is useful to understand melanoma metastasis and to develop diagnostic and therapeutic tools against this form of cancer. In this application, we propose experiments to extend our preliminary analysis of lncRNA expression to a larger patient population, and confirm the statistical significance of our preliminary data. Based on our preliminary observations, we hypothesize that differentially expressed lncRNAs are useful biomarkers for melanoma detection in humans. We propose the following Specific Aims to test our central hypothesis. Specific Aim 1: To test the hypothesis that differentially expressed melanoma-specific lncRNAs are useful biomarkers for melanoma detection in humans. Specific Aim 2: To identify the molecular function of melanoma upregulated lncRNA, AK023647. The major impact of this study is to demonstrate for the first time the involvement of lncRNA in development of melanoma, beyond the boundaries of protein-coding genes. The proposed study has the potential to have a high-impact on our understanding of melanoma development. PUBLIC HEALTH RELEVANCE: Melanoma is a skin cancer, often fatal when it metastasis to other organs. We propose to identify long noncoding RNA based molecular markers for melanoma early detection in humans.