The mortality rate of PCa in African American (AA) is 2-3 times higher than Caucasian American (CA) men. A number of studies demonstrated that high incidence and mortality rates of PCa among AA men might originate from genetic, lifestyle or socioeconomic-related factors. Molecular mechanisms underlying these discrepancies are still under investigation. The process of tumor growth and metastasis mainly depends on the ability of cancer cells to communicate with each other and with neighboring cells. Microvesicles (MVs) are small cell-derived extracellular bodies secreted by normal and tumor cells and they promote cell-cell communication. The cargo of these vesicles carries microRNAs mRNAs and proteins to recipient cells. MicroRNAs (miRNAs) are small non-coding regulatory RNAs that negatively regulate gene expression at the post-transcriptional level. However, their real physiological function of extracellular RNA (exRNA) including miRNAs, in PCa racial disparities is still obscure. Our previous study demonstrates that MV-derived onco-miRNAs contribute to PCa progression through transformation of patient-derived adipose stem cells. Importantly, we identified selective expression of a subset of putative onco-miRNAs in prostate tumors. Thus, altered onco-miRNAs expression could be a determinant factor for high PCa progression and mortality rates among AA men. Thus, we hypothesize that onco-miRNAs derived by prostate tumor microvesicles are critical to PC progression in AA men of PCa. This hypothesis will be tested by the following specific aims; 1) To investigate the expression levels of putative (miR-3613-3p and miR-3680-3p) and known (miR-125b, miR-130b and miR-155) onco-miRNAs in normal and PCa cells derived from AA and CA men as well as in human PCa specimens and 2) To examine the functional significance of these onco- miRNAs in mediating disease progression. This study is innovative, because it capitalizes on discovery of new functional roles for this putative onco-miRNAs and their relevant cellular target genes in PCa health disparity. Our expectation from this proposal is to understand the pleiotropic functions of these putative onco-miRNAs and clarify their implications in health disparity. Our preliminary results show that not only the expression of putative miRNAs (miR-3613-3p and miR-3680-3p) was higher in PCa cell lines versus normal cells but also in AA vs. CA patients. However, the expression of miRNA target genes (i.e. tumor suppressor genes; PDCD4 & LATS2) was low on in vitro and on human tissue level suggesting these miRNAs have an oncogenic activity. Our long-term goal is to explore the functional significance and potential clinical utilities of these putative miRNAs, as biomarkers or therapeutic targets, to improve the outcomes and quality of lives of patients suffering from this disease. The outcomes from this study will certainly benefit the PI by giving him the opportunity to acquire research support, exercise him to become independent investigator and inspire him to apply for independent research-supports (i.e. R01). In addition, scientific findings that will be obtained from this proposal may lead to discovery of new prognostic markers or therapeutic targets in PCa and definitely will address the reasons why African American men have more aggressive disease than other minorities.
The mortality rate of prostate cancer (PCa) in African American (AA) is 2-3 times higher than Caucasian American (CA) men. Molecular mechanisms underlying these discrepancies are still unknown. Microvesicles 'tiny bodies' secreted in our body were proved to carry extracellular/exosomal RNA (exRNA) to their target cells. miRNAs, one of exRNAs, expression could be a determinant factor for high PCa progression among AA men. We aim to investigate the expression and functional significance of putative miRNAs in normal and PCa derived from AA and CA men, and further establishing their clinical utilities.
|Panigrahi, Gati K; Ramteke, Anand; Birks, Diane et al. (2018) Exosomal microRNA profiling to identify hypoxia-related biomarkers in prostate cancer. Oncotarget 9:13894-13910|
|Ali, Hamdy E A; Lung, Pei-Yau; Sholl, Andrew B et al. (2018) Dysregulated gene expression predicts tumor aggressiveness in African-American prostate cancer patients. Sci Rep 8:16335|