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.

Public Health Relevance

This study will identify new mechanism of ovarian cancer development through several key proteins, and determine new roles and mechanism of these protein upregulation in mediating ovarian tumor growth, angiogenesis, and therapeutic resistance. We will also analyze correlation of these protein levels with ovarian cancer stages and survival. We expect to elucidate new mechanism of cancer development, to identify new therapeutic target(s), and/or to identify new biomarker(s) for ovarian cancer treatment and diagnostics in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193511-04
Application #
9664591
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2015-12-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Ge, Xin; Pan, Min-Hong; Wang, Lin et al. (2018) Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a/Bad/Bax axis. Cell Death Dis 9:1128
Jiang, Cheng-Fei; Shi, Zhu-Mei; Li, Dong-Mei et al. (2018) Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer. Mol Cancer 17:83
Wen, Yi-Yang; Liu, Wei-Tao; Sun, Hao-Ran et al. (2017) IGF-1-mediated PKM2/?-catenin/miR-152 regulatory circuit in breast cancer. Sci Rep 7:15897
Dai, Liping; Qu, Yanhong; Li, Jitian et al. (2017) 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. Oncotarget 8:36664-36673
Shi, Z-M; Wang, L; Shen, H et al. (2017) Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling. Oncogene 36:2577-2588
Qian, Xu; Li, Xinjian; Cai, Qingsong et al. (2017) Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy. Mol Cell 65:917-931.e6
Shen, Hua; Wang, Lin; Ge, Xin et al. (2016) MicroRNA-137 inhibits tumor growth and sensitizes chemosensitivity to paclitaxel and cisplatin in lung cancer. Oncotarget 7:20728-42
Lin, Yong; Ge, Xin; Wen, Yiyang et al. (2016) MiRNA-145 increases therapeutic sensibility to gemcitabine treatment of pancreatic adenocarcinoma cells. Oncotarget 7:70857-70868
Jiang, Cheng-Fei; Li, Dong-Mei; Shi, Zhu-Mei et al. (2016) Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis. Oncotarget 7:36940-36955
Wang, Lin; Jiang, Cheng-fei; Li, Dong-mei et al. (2016) MicroRNA-497 inhibits tumor growth and increases chemosensitivity to 5-fluorouracil treatment by targeting KSR1. Oncotarget 7:2660-71

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