title: Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
abstract: OBJECTIVE
  African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality compared with European American (EA) men. In addition to socioeconomic influences, biologic factors are believed to play a critical role in prostate cancer disparities. We investigated whether population-specific and -enriched miRNA-mRNA interactions might contribute to prostate cancer disparities.
  
  
  METHODS
  Integrative genomics was used, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis, and functional validation, to map miRNA-mRNA interactions associated with prostate cancer disparities.
  
  
  RESULTS
  We identified 22 AA-specific and 18 EA-specific miRNAs in prostate cancer versus patient-matched normal prostate, and 10 "AA-enriched/-depleted" miRNAs in AA prostate cancer versus EA prostate cancer comparisons. Many of these population-specific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed EGFR (or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs and miRNA-mRNA pairings. Novel miRNA-mRNA pairings were validated by qRT-PCR, Western blot, and/or IHC analyses in prostate cancer specimens. Loss/gain of function assays performed in population-specific prostate cancer cell lines confirmed miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ITPR2, and miR-34a/PPP2R2A as critical miRNA-mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA prostate cancer cells.
  
  
  CONCLUSIONS
  Our data suggest that AA-specific/-enriched miRNA-mRNA pairings may play a critical role in the activation of oncogenic pathways in AA prostate cancer. Our findings also suggest that miR-133a/MCL1, miR-513c/STAT1, and miR-96/FOXO3A may have clinical significance in the development of novel strategies for treating aggressive prostate cancer.
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Bi-Dar
authors.initials: BD
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ceniccola
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Medical Faculty Associates, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Ramez
authors.initials: R
authors.lastname: Andrawis
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: Cartilage Biology and Orthopedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Johng
authors.initials: J
authors.lastname: Rhim
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Olender
authors.affiliation: Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Anastas
authors.initials: A
authors.lastname: Popratiloff
authors.affiliation: Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Latham
authors.affiliation: Department of Statistics, The George Washington University, Washington, District of Columbia.
authors.forename: Yinglei
authors.initials: Y
authors.lastname: Lai
authors.affiliation: GW Cancer Institute, The George Washington University Medical Center, Washington, District of Columbia. Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Patierno
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia. nhlee@gwu.edu.
authors.forename: Norman H
authors.initials: NH
authors.lastname: Lee
mesh_terms: D001741:Black or African American / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D001706:Biopsy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger