The role of miR-211 and its target genes in melanoma development in humans.

描述（由申请人提供）：黑色素瘤是美国最致命的皮肤癌，发展为黑色素瘤的风险正在增加。如果及早发现，黑色素瘤的存活率非常高；然而，需要新的和更准确的诊断测试以及创新的治疗方法。皮肤黑色素瘤的组织病理学解释以及早期诊断仍然是皮肤病理学和外科病理学中最令人沮丧和困难的领域之一，因此，毫无疑问需要确定敏感和特异性的诊断标记。我们研究的长期目标是改善黑色素瘤的早期检测方法，并帮助预测早期皮肤病变发展为癌症的风险。这项研究具有重要意义，因为它关注了黑色素细胞特异性miRNA miR-211及其靶基因，这些基因可能是肿瘤发生的关键调节因子，可以用作黑色素瘤的早期诊断标志物。我们的中心假设是miR-211是黑色素瘤发展的早期指标，miR-211及其靶基因的表达失调参与了黑色素细胞向黑色素瘤的发展。我们计划通过以下实验来检验我们的中心假设，并完成本应用程序的总体目标。首先，我们将建立miR-211及其新的靶基因（IGFBP5, NFAT-5, RUNX2, IRF2BP2）的功能相关性，我们已经通过Affymetrix阵列鉴定并通过qRT-PCR验证。其次，我们将从表达miR-211的黑色素瘤细胞（A375/miR-211和WM1552C/miR-211）中挖掘现有的深度测序（RNA-seq）数据，以确定额外的靶基因和调控基因，以扩展miR-211信号通路。第三，我们将鉴定miR-211及其靶基因在不同分期黑色素瘤患者的组织样本（临床活检）、对照黑素细胞痣和正常皮肤中的表达。第四，我们将确定miR-211及其靶基因与黑色素瘤分期和发展的相关性。最后，这里提出的工作是创新的，因为它将确定miR-211及其靶基因在黑色素瘤中的作用，并提供证据表明miR-211和靶基因是能够对这种通常致命的疾病进行更精细分类的早期预后标记。本研究的转化影响将是提高黑色素瘤的早期检测，帮助预测黑色素瘤的风险，区分良性病变和癌前病变。

DESCRIPTION (provided by applicant): Melanoma is the most lethal form of skin cancer in the United States and the risk of developing melanoma is increasing. The survival rate for melanoma is very high when detected early; however, there is a need for new and more accurate diagnostic tests, as well as innovative therapies. The histopathologic interpretation of cutaneous melanoma coupled with earlier diagnosis remains one the most frustrating and difficult areas in dermatopathology and surgical pathology and therefore, there is an unquestioned need to identify sensitive and specific diagnostic markers. The long-term goal of our research is to improve early detection methods for melanoma, and to help predict the risk that early skin lesions will progress to cancer. The proposed study is significant, as it focuses o a melanocyte specific miRNA, miR-211, and its target genes that may be key regulators for tumorigenesis and can be used as early diagnostic markers for melanoma. Our central hypothesize is that miR-211 is an early indicator of the development of melanoma, and dysregulated expression of miR-211 and its target genes are involved in the progression of melanocytes to melanomas. We plan to test our central hypothesis and accomplish the overall objective of this application by pursing the following experiments. First, we will establish the functional relevance of miR-211 and its new target genes (IGFBP5, NFAT-5, RUNX2, IRF2BP2) which we have identified by Affymetrix array and validated by qRT-PCR. Second, we will mine the existing deep-sequencing (RNA-seq) data from miR-211- expressing melanoma cells (A375/miR-211, and WM1552C/miR-211) to identify additional target and regulatory genes to expand the miR- 211 signaling pathway. Third, we will identify the expression of miR-211 and its target genes in tissue samples (clinical biopsies) from patients with differentially staged melanoma, and in control melanocytic nevi and normal skin. Fourth, we will determine the relevance of miR-211 and its target genes to melanoma staging and development. Finally, the work proposed here is innovative, because it will identify the role of miR-211 and its target genes in melanoma and provide evidence that miR-211 and target genes are early prognostics markers capable of finer classification of this often-fatal disease. The translational impact of ths study will be to improve early melanoma detection, to help predict the risk of melanoma, and to distinguish benign lesion and precancerous lesions.