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: 10304003
• 负责人: Jun He
• 金额: $ 32.12万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304003
• 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（由申请人提供）：卵巢癌是女性癌症相关死亡的第五大原因。然而，卵巢癌的发生机制及其对治疗的反应仍有待阐明。我们的初步研究结果表明，卵巢癌细胞产生更高水平的活性氧（ROS）通过NOX 4过表达相比，永生化的正常卵巢上皮细胞。在癌细胞中敲低N 0X 4降低了ROS的产生，以及HER 2、HER 3和ATG 14的表达。为了测试NOX 4在卵巢癌细胞中是如何上调的，我们发现HIF-1和p70 S6 K1在这些细胞中被激活。已知HIF-1和p70 S6 K1被癌基因如PI 3 K和Ras以及肿瘤抑制因子如PTEN和p53的突变激活。我们的初步结果表明，HIF-1和p70 S6 K1诱导NOX 4过表达。我们假设HIF-1和p70 S6 K1诱导NOX 4过表达，进而通过miR-199 a/miR-152抑制诱导HER 2/HER 3共表达和ATG 14表达，导致卵巢肿瘤生长、血管生成和治疗耐药性。我们将使用多学科的方法，包括分子生物学，动物模型和人类癌症组织分析，通过三个具体目标来验证我们的假设。目的1将确定HIF-1和p70 S6 K1是否诱导NOX 4表达，这反过来又介导HER 2和HER 3共表达; NOX 4是否通过HER 2和HER 3调节曲妥珠单抗治疗抗性，并通过诱导自噬和ATG 14表达调节放射治疗抗性。我们将操纵HIF-1，p70 S6 K1，NOX 4和其他分子在细胞中的表达，并确定这些分子在曲妥珠单抗和放射治疗反应中的作用。目的2将使用原位卵巢肿瘤模型确定NOX 4是否通过miR-199 a抑制通过HER 2和HER 3共表达诱导卵巢肿瘤生长，并使用图像引导放射治疗确定NOX 4是否通过ATG 14影响放射治疗效果。目的3将确定NOX 4是否通过HER 2，HER 3和miR-199 a抑制来调节肿瘤血管生成;并研究NOX 4，ROS，HER 2，HER 3，miR-199 a和miR-152的水平是否与晚期卵巢癌分期和生存相关。总之，从本申请获得的这些结果将建立N 0X 4信号传导在调节卵巢癌发展中的新的分子机制，并提供关于N 0X 4如何调节辐射和曲妥珠单抗治疗抗性的原理证明。这些结果将为通过靶向NOX 4、HER 2/HER 3共表达和/或ATG 14来设计用于卵巢癌治疗的新治疗方法提供基础。这些研究还将使用更高水平的NOX 4、ROS、ATG 14和/或HER 2/HER 3共表达提供新的生物标志物，以预测未来的晚期卵巢癌分期、放射或/和曲妥珠单抗治疗抗性。

项目成果

Serological proteome analysis approach-based identification of ENO1 as a tumor-associated antigen and its autoantibody could enhance the sensitivity of CEA and CYFRA 21-1 in the detection of non-small cell lung cancer.

基于血清学蛋白质组分析方法鉴定ENO1作为肿瘤相关抗原及其自身抗体可增强CEA和CYFRA 21-1检测非小细胞肺癌的敏感性

• DOI: 10.18632/oncotarget.17067
• 发表时间: 2017-05-30
• 期刊: Oncotarget
• 作者: Dai L;Qu Y;Li J;Wang X;Wang K;Wang P;Jiang BH;Zhang J
• 通讯作者: Zhang J

Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.

雌激素调节 miRNA 表达：雌激素受体和 miR-124/AKT2 在肿瘤生长和血管生成中的意义

• DOI: 10.18632/oncotarget.9230
• 发表时间: 2016-06-14
• 期刊: Oncotarget
• 作者: Jiang CF;Li DM;Shi ZM;Wang L;Liu MM;Ge X;Liu X;Qian YC;Wen YY;Zhen LL;Lin J;Liu LZ;Jiang BH
• 通讯作者: Jiang BH

MicroRNA-497 inhibits tumor growth and increases chemosensitivity to 5-fluorouracil treatment by targeting KSR1.

MicroRNA-497 通过靶向 KSR1 抑制肿瘤生长并增加对 5-氟尿嘧啶治疗的化疗敏感性

• DOI: 10.18632/oncotarget.6545
• 发表时间: 2016-01-19
• 期刊: Oncotarget
• 作者: Wang L;Jiang CF;Li DM;Ge X;Shi ZM;Li CY;Liu X;Yin Y;Zhen L;Liu LZ;Jiang BH
• 通讯作者: Jiang BH

Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer.

雌激素诱导的 miR-196a 升高通过靶向乳腺癌中的 SPRED1 促进肿瘤生长和转移

• DOI: 10.1186/s12943-018-0830-0
• 发表时间: 2018-04-23
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Jiang CF;Shi ZM;Li DM;Qian YC;Ren Y;Bai XM;Xie YX;Wang L;Ge X;Liu WT;Zhen LL;Liu LZ;Jiang BH
• 通讯作者: Jiang BH

Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a/Bad/Bax axis.

缺氧介导的线粒体凋亡抑制通过 miR-26a/Bad/Bax 轴诱导替莫唑胺治疗耐药

• DOI: 10.1038/s41419-018-1176-7
• 发表时间: 2018-11-13
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Ge X;Pan MH;Wang L;Li W;Jiang C;He J;Abouzid K;Liu LZ;Shi Z;Jiang BH
• 通讯作者: Jiang BH