Prostate cancer (PCa) is the most common cancer in men in the United States, which disproportionately affects African Americans (AA) with higher incidence, advanced disease and worse prognosis. MicroRNAs (miRNAs) are non-coding RNAs that represent universal gene regulatory mechanism exerting its effect primarily by binding to 3'UTR of target and affect cell survival, proliferation, cancer initiation, development and metastasis. We recently reported differential expression of miRNAs in PCa tissues and body fluids. In this proposal, we present preliminary data on selected two miRNAs that are downregulated in age/disease matched African American (AA) 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 aggressive phenotype. Further these miRNAs could be used as biomarkers to distinguish between indolent vs. aggressive disease (predominant in AAs) and serve as novel therapeutic targets.
The specific aims of this proposal are: (1) 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; (2) 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); (3) 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 basis of PCa pathogenesis, disparity and understanding their biological implications will significantly impact diagnosis and treatment development for aggressive PCa common in African American men.
The proposal will characterize selected microRNAs that are downregulated in African American (AA) prostate cancer (PCa) tissues when compared with Caucasian (CA) PCa. Their characterization will provide basic mechanistic insights into their role in prostate carcinogenesis, as biomarker and therapeutic targets. In the long term, these studies could have significant public health consequences, as involvement of these miRNAs in AA PCa will support their development as molecular targets and biomarkers for early detection, prevention and treatment of aggressive PCa common in AA men.
|Ramalinga, Malathi; Roy, Arpita; Srivastava, Anvesha et al. (2015) MicroRNA-212 negatively regulates starvation induced autophagy in prostate cancer cells by inhibiting SIRT1 and is a modulator of angiogenesis and cellular senescence. Oncotarget 6:34446-57|