Epidermal growth factor regulation of miR-125a promotes invasive ovarian cancer

描述(由申请人提供)：我的长期职业目标是成为一个学术中心的教员，在那里我将研究microRNAs(MiRNAs)对卵巢癌转移的贡献。我目前的职业目标是在卵巢癌基因调控方面建立一个独立的研究项目，获得成为一名独立科学家所需的技能，并获得作为教师所需的指导和教学技能。我正在新墨西哥大学劳里·哈德森博士的实验室进行我的研究，在那里我们可以获得最先进的基因组学、显微镜和流式细胞术资源。北卡罗来纳大学是NCI指定的癌症中心，拥有不同的研究人员群体，他们的合作和多学科努力创造了丰富的研究环境。基于她在研究教育方面的强大背景，哈德森博士在UNM的实验室是过渡到教员职位的理想环境。我的项目目标是了解miRNAs的调控如何促进卵巢癌的转移。表皮生长因子受体(EGFR)与晚期卵巢癌相关，调节细胞侵袭，促进基因表达的广泛变化。因此，我将研究EGFR信号在卵巢癌转移过程中对miRNAs的调控。我假设EOF受体信号通过在转录水平上协调调节包括miR-125a在内的一组miRNAs来促进卵巢癌的侵袭。我确定EGF治疗降低了mir125a的表达，miR-125a调节卵巢肿瘤细胞中的转移相关靶点。以下特定目的将验证这一假设：1)研究EGFR信号如何转录调控卵巢肿瘤细胞中miRNA的表达；2)评估miR-125a通过调节侵袭靶点对侵袭潜能的贡献；3)分析人类肿瘤和恶性腹水中miR-125a的表达，以确定miR-125a在卵巢癌中的表达是否发生了变化。这些新的研究将为miRNAs在卵巢癌中的功能作用提供证据。相关性：绝大多数被诊断为卵巢癌的女性都有晚期转移性疾病(70%)，导致预后不良。EGFR途径与不良的患者预后密切相关。了解在癌症中独特调节的microRNAs(通过EGFR等途径)如何在促进肿瘤进展中发挥作用，将有助于开发新的诊断和治疗靶点。

DESCRIPTION (provided by applicant): My long-term career goal is to become a faculty member at an academic center where I will investigate the contribution of microRNAs (miRNAs) to ovarian cancer metastasis. My current career goals are to build an independent research program in the control of ovarian cancer gene regulation, gain the skills I need to be an independent scientist, and acquire the mentorship and teaching skills necessary as faculty member. I am conducting my research in the lab of Dr. Laurie Hudson at the University of New Mexico where we have access to state-of-the-art genomics, microscopy, and flow cytometry resources. UNM is a NCI designated Cancer Center and home to diverse group of investigators whose collaborative and multi-disciplinary efforts generate a rich research environment. Based on her strong background in research education, Dr. Hudson's lab at UNM is the ideal environment to support by transition to a faculty position. My project objective is to understand how regulation of miRNAs contributes to ovarian cancer metastasis. The epidermal growth factor receptor (EGFR) is associated with advanced ovarian cancer, regulates cell invasion, and promotes broad changes in gene expression. Therefore, I will investigate regulation of miRNAs by EGFR signaling in the metastatic progression of ovarian cancer. I hypothesize that EOF receptor signaling promotes ovarian cancer invasion by coordinately regulating a cohort of miRNAs including miR-125a at the transcriptional level. I determined that EGF treatment reduces mir125a expression and miR-125a regulates metastasis relevant targets in ovarian tumor cells. The following specific aims will test the hypothesis: 1) investigate how EGFR signaling transcriptionally regulates miRNA expression in ovarian tumor cells, 2) evaluate the contribution of miR-125a to invasive potential by regulating invasive targets, and 3) analyze human tumors and malignant ascites for miR-125a expression to establish whether the expression of miR-125a is altered in ovarian cancer. These novel studies will provide evidence for a functional role for miRNAs in ovarian cancer. Relevance: The vast majority of women diagnosed with ovarian cancer have advanced metastatic disease (>70%) leading to poor prognosis. The EGFR pathway is strongly associated with poor patient outcome. Understanding how microRNAs uniquely regulated in cancer (through pathways such as EGFR) function in promoting tumor progression will enable development of novel diagnostic and therapeutic targets.