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.
|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|
|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|
|Guo, Jian-Ping; Coppola, Domenico; Cheng, Jin Q (2011) IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. J Biol Chem 286:37389-98|
|Zhao, Jian-Jun; Lin, Jianhong; Lwin, Tint et al. (2010) microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood 115:2630-9|
|Guo, Jian-Ping; Shu, Shao-Kun; Esposito, Nicole N et al. (2010) IKKepsilon phosphorylation of estrogen receptor alpha Ser-167 and contribution to tamoxifen resistance in breast cancer. J Biol Chem 285:3676-84|
|Kim, Donghwa; Shu, Shaokun; Coppola, Marc D et al. (2010) Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One 5:e9616|
|Shu, Shao-Kun; Liu, Qiyuan; Coppola, Domenico et al. (2010) Phosphorylation and activation of androgen receptor by Aurora-A. J Biol Chem 285:33045-53|
|Yuan, Zengqiang; Kim, Donghwa; Shu, Shaokun et al. (2010) Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem 285:3815-24|
|Kim, Donghwa; Sun, Mei; He, Lili et al. (2010) A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation. J Biol Chem 285:8383-94|
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