MicroRNAs in Human Ovarian Cancer

在西方世界，卵巢癌是妇科恶性肿瘤的主要死因。它的高度 死亡率是因为大多数患者(~75%)是在疾病的晚期被诊断为 腹内播散性转移。铂类药物化疗后的去瘤手术 这些方案被认为是这些患者的标准护理。然而，尽管最初的应答率为65%-80% 对于一线化疗，大多数卵巢癌复发。对进一步化疗的获得性耐药是 一般对治疗失败负责，导致晚期患者的总体5年存活率仅为25%左右。 卵巢癌分期。因此，迫切需要确定新的分子负责 化疗耐药和卵巢癌的发展，从而导致新的靶向治疗。MicroRNAs (MiRNA)是一类在系统发育上保守的小RNA，在 调节细胞的存活、增殖、分化和血管生成。积累的研究表明， 在人类恶性肿瘤中，miRNAs经常被解除调控，其功能可能是“癌基因”，也可能是“肿瘤” 此外，miRNA表达特征与特定的临床癌症有很好的相关性 特征，可用于正常组织和癌组织的分类以及恶性肿瘤的亚型。我们的 初步数据显示，在人卵巢癌中miRNAs频繁上调或下调，其中一些 它们，特别是miR-214，参与了化疗耐药和转移，并具有致癌活性。基座 根据这些初步数据以及每个miRNA负向调控数百个基因的事实，我们 假设miRNAs在卵巢癌的发生、腹内扩散和卵巢癌的发生中起重要作用 化疗耐药，可能成为卵巢癌的治疗靶点。因此，这个项目的目标是 目的是确定miRNAs作为卵巢癌的致病因子和治疗靶点。测试我们的 假设并实现我们的目标，我们将1)确定miR-214在卵巢中过表达的机制 2)检测miR-214功能增减对卵巢肿瘤表型的影响 肿瘤细胞和miR-214在OSE细胞中的致癌活性；3)决定miR-214基因上调的后果 4)验证miR-214靶向基因和 确定miR-214在肿瘤发生中的作用机制。

Ovarian carcinoma is the leading cause of death from gynecological malignancies in the western world. Its high death rate is a result of the fact that most patients (~75%) are diagnosed at an advanced stage of disease with disseminated intra-abdominal metastasis. Debulking surgery followed by platinum-based chemotherapy schemes is considered standard care for these patients. However, despite an initial response rate of 65%-80% to first-line chemotherapy, most ovarian carcinomas relapse. Acquired resistance to further chemotherapy is generally responsible for treatment failure, resulting in an overall 5-year survival rate of only about 25% for late- stage ovarian cancer. Thus, there is urgent need to identify novel molecules that are responsible for chemoresistance and ovarian cancer development, and thus lead to new targeted therapy. MicroRNAs (miRNA) are a class of small RNAs that are phylogenetically conserved and play important roles in the regulation of cell survival, proliferation, differentiation and angiogenesis. Accumulated studies shows that miRNAs are frequently deregulated in human malignancy and function as either "oncogenes" or "tumor suppressor genes". In addition, miRNA expression signatures correlate well with specific clinical cancer characteristics and can be used to classify normal and cancerous tissues as well as subtype of malignancy. Our preliminary data show frequent upregulation or downregulation of miRNAs in human ovarian cancer, some of which, especially miR-214, are involved in chemoresistance and metastasis and have oncogenic activity. Based on these preliminary data and the fact that each miRNA negatively regulates hundreds of genes, we hypothesize that miRNAs play significant role in ovarian carcinogenesis, intra-abdominal dissemination and chemoresistance and could be therapeutic targets for human ovarian cancer. Thus, the objective of this project is to determine the miRNAs as pathogenetic factors and therapeutic targets in ovarian cancer. To test our hypothesis and achieve our goal, we will 1) determine the mechanism of overexpression of miR-214 in ovarian cancer; 2) examine the effects of miR-214 gain- and loss-of-function on the neoplastic phenotypes of ovarian cancer cells and the oncogenic activity of miR-214 in OSE cells; 3) determine the consequence of miR-214 gain of function on ovarian tumorigenesis in transgenic mice and 4) validate the miR-214 targeted genes and determine the mechanism of miR-214 in oncogenesis.