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Clin Cancer Res. 2015 Nov 1;21(21):4970-84. doi: 10.1158/1078-0432.CCR-14-1566. Epub 2015 Jun 18.

Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.

Author information

1
Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
2
Medical Faculty Associates, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
3
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
4
Cartilage Biology and Orthopedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
5
Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
6
Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
7
Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
8
Department of Statistics, The George Washington University, Washington, District of Columbia.
9
GW Cancer Institute, The George Washington University Medical Center, Washington, District of Columbia. Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
10
Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia. nhlee@gwu.edu.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
26089375
PMCID:
PMC4631799
DOI:
10.1158/1078-0432.CCR-14-1566
[Indexed for MEDLINE]
Free PMC Article

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