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.
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.
|Li, Y; Lauriola, M; Kim, D et al. (2016) Adenomatous polyposis coli (APC) regulates miR17-92 cluster through Î²-catenin pathway in colorectal cancer. Oncogene 35:4558-68|
|Richards, Edward J; Zhang, Gu; Li, Zhu-Peng et al. (2015) Long non-coding RNAs (LncRNA) regulated by transforming growth factor (TGF) Î²: LncRNA-hit-mediated TGFÎ²-induced epithelial to mesenchymal transition in mammary epithelia. J Biol Chem 290:6857-67|
|Richards, Edward J; Permuth-Wey, Jennifer; Li, Yajuan et al. (2015) A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer. Oncotarget 6:34745-57|
|Zheng, X Q; Guo, J P; Yang, H et al. (2014) Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERÎ± in breast cancer. Oncogene 33:4985-96|
|Kong, W; He, L; Richards, E J et al. (2014) Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene 33:679-89|
|Guo, J; Kim, D; Gao, J et al. (2013) IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer. Oncogene 32:151-9|
|Guo, Jian-Ping; Tian, Wei; Shu, Shaokun et al. (2013) IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function. PLoS One 8:e63636|
|Cui, Gaofeng; Park, Sungman; Badeaux, Aimee I et al. (2012) PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53. Nat Struct Mol Biol 19:916-24|
|Park, Sungman; Kim, Donghwa; Dan, Han C et al. (2012) Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53. J Biol Chem 287:11151-63|
|Xu, Cheng-Xiong; Xu, Meng; Tan, Lei et al. (2012) MicroRNA miR-214 regulates ovarian cancer cell stemness by targeting p53/Nanog. J Biol Chem 287:34970-8|
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