Prostate cancer (PCa) is the most common cancer in men in the United States and disproportionately affects African Americans (AA), with higher incidence, advanced disease and worse prognosis. MicroRNAs (miRNAs) are non-coding RNAs that represent a universal gene regulatory mechanism exerting its effect primarily by binding to the 3’UTR of the target and affecting cell survival, proliferation, cancer initiation, development and metastasis.
We recently reported differential expression of miRs in PCa tissues and body fluids. In this proposal, we present preliminary data on two selected miRNAs that are down-regulated in age/disease-matched African American (AA) PCa tissues when compared with Caucasian (CA) PCa tissues. We present preliminary data on modulation cancer cell growth, migration, anoikis, angiogenesis and modulation of EMT signaling. We have preliminarily identified several miRNA targets that may explain miRNA mechanisms in PCa progression. We report miRNA modulation of JNK1-Sp1 signaling, which is known to modulate angiogenesis and metastasis.
We hypothesize that differential loss of selected microRNAs in AA PCa deregulates an intricate signaling network, leading to an aggressive phenotype. Further, these miRs could be used as biomarkers to distinguish between indolent versus aggressive disease (predominant in AAs) and serve as novel therapeutic targets.
The specific aims of this proposal are to:
- Study the clinical significance of microRNAs and their targets in age/race-matched PCa tissues and their adjacent benign regions and disease staged PCa TMAs;
- Delineate the mechanisms of miR-214 and miR-99b in PCa signaling: to validate miRNA targets and delineate signaling mechanisms by generating miRNA gene deletions in AA and CA prostate cells by genome editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (CAS) nuclease Cas9;
- Investigate the role of microRNAs in experimental prostate carcinogenesis in vitro and in vivo by studying their gain and loss of function in AA and CA prostate cancer cells and in vivo by examining the effects on tumor growth and metastasis in an orthotopic mouse model.
Recognizing miRNAs as a basis of PCa pathogenesis and disparity and understanding their biological implications will significantly impact diagnosis and treatment development for the aggressive PCa common in African American men.