MicroRNAs in Human Ovarian Cancer

人类卵巢癌中的 MicroRNA

• 批准号: 8065532
• 负责人: Jin Q Cheng
• 金额: $ 33.61万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065532
• 关键词: Apoptosis; Behavior; Cancer Patient; Cancerous; Cause of Death; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cell physiology; Characteristics; Clinical; Data; Death Rate; Development; Diagnosis; Diagnostic; Disease; Down-Regulation; Early Diagnosis; Ectopic Expression; Epithelial Cells; Gene Targeting; Genes; Goals; Growth; Health; Human; Intervention; Intra-abdominal; Lead; Lysophospholipids; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Messenger RNA; Metastatic Malignant Neoplasm to the Ovary; MicroRNAs; Molecular Profiling; Neoplasm Metastasis; Normal Cell; Nucleotides; Oncogenes; Oncogenic; Operative Surgical Procedures; Ovarian; Ovarian Carcinoma; Ovary; Patients; Phenotype; Plasma; Platinum; Play; Primary Neoplasm; Process; Prognostic Marker; Receptor Gene; Regulation; Relapse; Resistance; Role; Scheme; Screening for Ovarian Cancer; Serum; Simian virus 40; Small RNA; Staging; Surface; Survival Rate; Testing; Tissues; Transcriptional Regulation; Transgenic Mice; Treatment Failure; Tumor Debulking; Tumor Markers; Tumor Suppressor Genes; Up-Regulation; Western World; Xenograft procedure; angiogenesis; base; cancer cell; cancer therapy; carcinogenesis; cell motility; chemotherapy; epithelial to mesenchymal transition; gain of function; loss of function; lysophosphatidic acid; malignant phenotype; mouse model; mullerian-inhibiting hormone; neoplastic; novel; outcome forecast; overexpression; promoter; response; standard care; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): 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 gene and determine the mechanism of miR-214 in oncogenesis. PUBLIC HEALTH RELEVANCE: MicroRNA in Human Ovarian Cancer Ovarian carcinoma is the leading cause of death from gynecological malignancies. Its high death rate is a result of the fact that most patients (~75%) are diagnosed at an advanced stage of disease. 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 develop tumor markers for early detection and identify novel molecules that are responsible for chemoresistance and ovarian cancer development, and thus lead to new targeted therapy. We have recently identified frequent alterations of a class small nucleotides, called microRNAs, in human ovarian cancer. Some of these microRNAs are involved in chemoresistance and drive "normal" cells to malignant behavior. We also detected microRNA in human ovarian cancer plasma. Based on these preliminary results, we will investigate if the microRNAs could be diagnostic/prognostic markers, therapeutic targets and causal factors in human ovarian cancer. These studies will have significant impact on ovarian cancer detection and treatment.

描述（由申请人提供）：卵巢癌是西方世界妇科恶性肿瘤死亡的主要原因。其高死亡率是因为大多数患者（约 75%）在诊断时已处于疾病晚期，并伴有播散性腹腔内转移。减瘤手术后进行铂类化疗方案被认为是这些患者的标准护理。然而，尽管一线化疗的初始反应率为 65%-80%，但大多数卵巢癌都会复发。对进一步化疗的获得性耐药通常是治疗失败的原因，导致晚期卵巢癌的总体 5 年生存率仅为 25% 左右。因此，迫切需要鉴定导致化疗耐药和卵巢癌发展的新分子，从而产生新的靶向治疗。 MicroRNA（miRNA）是一类系统发育上保守的小RNA，在细胞存活、增殖、分化和血管生成的调节中发挥重要作用。累积的研究表明，miRNA 在人类恶性肿瘤中经常失调，并充当“癌基因”或“肿瘤抑制基因”。此外，miRNA 表达特征与特定的临床癌症特征密切相关，可用于对正常组织和癌组织以及恶性肿瘤亚型进行分类。我们的初步数据显示，人类卵巢癌中 miRNA 频繁上调或下调，其中一些 miRNA，尤其是 miR-214，参与化疗耐药和转移，并具有致癌活性。基于这些初步数据以及每个 miRNA 对数百个基因负调控的事实，我们假设 miRNA 在卵巢癌发生、腹腔内传播和化疗耐药中发挥重要作用，并可能成为人类卵巢癌的治疗靶点。因此，该项目的目标是确定 miRNA 作为卵巢癌的致病因素和治疗靶点。为了检验我们的假设并实现我们的目标，我们将1）确定卵巢癌中miR-214过度表达的机制； 2）检查miR-214功能获得和丧失对卵巢癌细胞肿瘤表型的影响以及miR-214在OSE细胞中的致癌活性； 3) 确定 miR-214 功能获得对转基因小鼠卵巢肿瘤发生的影响，4) 验证 miR-214 靶向基因并确定 miR-214 在肿瘤发生中的机制。公共卫生相关性：人类卵巢癌中的 MicroRNA 卵巢癌是妇科恶性肿瘤死亡的主要原因。其高死亡率是因为大多数患者（约 75%）在疾病晚期才被诊断出来。尽管一线化疗的初始反应率为 65%-80%，但大多数卵巢癌都会复发。对进一步化疗的获得性耐药通常是治疗失败的原因，导致晚期卵巢癌的总体 5 年生存率仅为 25% 左右。因此，迫切需要开发用于早期检测的肿瘤标志物，并鉴定导致化疗耐药和卵巢癌发展的新分子，从而带来新的靶向治疗。我们最近在人类卵巢癌中发现了一类小核苷酸（称为 microRNA）的频繁改变。其中一些 microRNA 参与化学耐药性并驱动“正常”细胞发生恶性行为。我们还在人卵巢癌血浆中检测到了 microRNA。基于这些初步结果，我们将研究 microRNA 是否可以作为人类卵巢癌的诊断/预后标志物、治疗靶点和致病因素。这些研究将对卵巢癌的检测和治疗产生重大影响。