NOX4 mediates oxidative stress in ovarian tumor growth and treatment response

NOX4 介导卵巢肿瘤生长和治疗反应中的氧化应激

• 批准号: 9187916
• 负责人: BingHua Jiang
• 金额: $ 10.6万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187916
• 关键词: Affect; Alternative Splicing; Animal Model; Autophagocytosis; Biological Markers; Cancer Diagnostics; Cancer Etiology; Cells; Cessation of life; Cohort Studies; Development; Down-Regulation; ERBB2 gene; ERBB3 gene; Endothelial Cells; Epithelial Cells; Experimental Models; Feedback; Future; Gene Amplification; Gene Dosage; Human; KDR gene; Knock-out; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Molecular Biology; Mutation; NADPH Oxidase; Oncogenes; Ovarian; Ovary; Oxidative Stress; PTEN gene; Play; Production; Protein Isoforms; Proteins; Radiation; Radiation therapy; Reactive Oxygen Species; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; TP53 gene; Testing; Tissues; Transcriptional Activation; Translational Regulation; Trastuzumab; Tumor Angiogenesis; Tumor Suppressor Proteins; Up-Regulation; Vascular Endothelial Growth Factors; Woman; angiogenesis; cancer cell; cancer therapy; design; hypoxia inducible factor 1; image guided radiation therapy; in vivo; interdisciplinary approach; knock-down; new therapeutic target; novel; novel therapeutic intervention; ovarian neoplasm; overexpression; p65; paracrine; public health relevance; radiation resistance; therapy resistant; treatment effect; treatment response; tumor; tumor growth

 DESCRIPTION (provided by applicant): Ovarian cancer represents the fifth leading cause of cancer-related death among women. However, the mechanisms of ovarian cancer development and its response to treatment remain to be elucidated. Our preliminary results show that ovarian cancer cells generate higher levels of reactive oxygen species (ROS) through NOX4 overexpression compared to immortalized normal ovary epithelial cells. Knockdown of NOX4 in cancer cells decreased ROS production, as well as expression of HER2, HER3 and ATG14. To test how NOX4 is upregulated in ovarian cancer cells, we find that HIF-1 and p70S6K1 are activated in these cells. It is known that HIF-1 and p70S6K1 are activated by oncogenes, such as PI3K and Ras, and by mutations of tumor suppressors, such as PTEN and p53. Our preliminary results indicate that HIF-1 and p70S6K1 induce NOX4 overexpression. We hypothesize that HIF-1 and p70S6K1 induce NOX4 overexpression, which in turn induces HER2/HER3 co-expression and ATG14 expression through miR-199a/miR-152 suppression, leading to ovarian tumor growth, angiogenesis, and therapeutic resistance. We will use multidisciplinary approaches, including molecular biology, animal models and human cancer tissue analysis, to test our hypothesis through three specific aims. Aim 1 will determine whether HIF-1 and p70S6K1 induce NOX4 expression, which in turn mediates HER2 and HER3 co-expression; whether NOX4 regulates trastuzumab treatment resistance through HER2 and HER3, and regulates radiation treatment resistance through induction of autophagy and ATG14 expression. We will manipulate expression of HIF-1, p70S6K1, NOX4 and other molecules in the cells and define the roles of these molecules in trastuzumab and radiation treatment responses. Aim 2 will determine whether NOX4 induces ovarian tumor growth through HER2 and HER3 co-expression via miR-199a suppression using an orthotopic ovarian tumor model, and determine whether NOX4 affects radiation treatment effect via ATG14 using image-guided radiotherapy. Aim 3 will determine whether NOX4 regulates tumor angiogenesis through HER2, HER3, and miR-199a suppression; and investigate whether levels of NOX4, ROS, HER2, HER3, miR-199a, and miR-152 correlate with advanced ovarian cancer stages and survival. Taken together, these results obtained from this application will establish a novel molecular mechanism of NOX4 signaling in regulating ovarian cancer development and provide proof- of-principle as to how NOX4 regulates radiation and trastuzumab treatment resistance. These results will provide the basis for designing a new therapeutic approach by targeting NOX4, HER2/HER3 co-expression, and/or ATG14 for ovarian cancer therapy. These studies will also provide new biomarker(s) using higher levels of NOX4, ROS, ATG14, and/or HER2/HER3 co-expression to predict advanced ovarian cancer stages, radiation or/and trastuzumab treatment resistance in the future.

 描述（由适用提供）：卵巢癌是女性与癌症相关死亡的第五大主要原因。但是，卵巢癌发展的机制及其对治疗的反应尚待阐明。我们的初步结果表明，与永生的正常卵巢上皮细胞相比，卵巢癌细胞通过NOX4过表达产生更高水平的活性氧（ROS）。癌细胞中NOX4的敲低降低了ROS的产生，以及HER2，HER3和ATG14的表达。为了测试卵巢癌细胞中NOX4的更新，我们发现在这些细胞中激活了HIF-1和P70S6K1。众所周知，HIF-1和P70S6K1被癌基因（例如PI3K和RAS）激活，以及肿瘤补充剂（例如PTEN和P53）的突变。我们的初步结果表明HIF-1和P70S6K1诱导NOX4过表达。我们假设HIF-1和P70S6K1诱导NOX4过表达，进而通过miR-199a/miR-152抑制诱导HER​​2/HER3共表达和ATG14表达，从而导致卵巢肿瘤的生长，血管生成，血管生成和热耐药性。我们将使用包括分子生物学，动物模型和人类癌组织分析在内的多学科方法，通过三个特定目标来检验我们的假设。 AIM 1将确定HIF-1和P70S6K1是否影响NOX4的表达，这又会介导HER2和HER3共表达。 NOX4是否通过HER2和HER3调节曲妥珠单抗治疗耐药性，并通过诱导自噬和ATG14表达来调节辐射治疗耐药性。我们将操纵细胞中HIF-1，p70S6K1，NOX4和其他分子的表达，并定义这些目标2的作用2将决定NOX4是否通过HER2和HER3 Co-Excression诱导卵巢肿瘤的生长和MiR-199a的表达，并使用Orthopic肿瘤模型使用NOX14抑制NOX14，并确定NOX14是否会通过hADID CARTIDERS IMPARTIONT ATG效应，并通过ATG效应进行ATG效应。 AIM 3将确定NOX4是否通过HER2，HER3和MIR-199A抑制来调节肿瘤血管生成；并研究NOX4，ROS，HER2，HER3，MIR-199A和MIR-152的水平是否与晚期卵巢癌阶段和生存有关。综上所述，从本应用中获得的这些结果将在调节卵巢癌发育中建立NOX4信号传导的新型分子机制，并提供有关NOX4如何调节辐射和曲妥珠单抗治疗耐药性的原则证明。这些结果将为靶向NOX4，HER2/HER3共表达和/或ATG14用于卵巢癌疗法设计新的治疗方法的基础。这些研究还将使用更高水平的NOX4，ROS，ATG14和/或HER2/HER3共表达提供新的生物标志物，以预测未来的晚期卵巢癌阶段，辐射或/和曲妥珠单抗治疗的耐药性。