Validation and Interrogation of Differentially Expressed and Alternately Spliced Genes in African American Prostate Cancer
Technical Report,30 Sep 2018,29 Sep 2019
Duke University Durham United States
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We have discovered RNA splicing as a novel mechanism underlying tumor aggressiveness and drug resistance in prostate cancer PCa in African American AA patients. To interrogate further the contribution of RNA splicing to PCa disparities, we have collected blood and tissue specimens of varying Gleason grade from AA and white patients for study. In addition, we have identified single nucleotide polymorphisms SNPs predicted to regulate RNA splicing in race-related alternatively spliced genes involved in stemness that associate with race-related PCa risk or PCa survival and genome-wide SNPs predicted to regulate RNA splicing that associate with advanced PCa. Furthermore, we have developed a splice-switching oligonucleotide SSO that specifically inhibits expression of the pathogenic androgen receptor AR-variant 7 V7, while maintaining expression of full-length AR, which has therapeutic value. This SSO inhibits proliferation of PCa cells and restores sensitivity to an AR inhibitor. It can be delivered directly to PCa cells without transfection reagent. Ultimately, this study will elucidate further molecular mechanisms underlying PCa in AA men and aid in development of new approaches for prevention and treatment that will mitigate PCa disparities for AAs and improve outcomes for men of all races with aggressive disease.
- Medicine and Medical Research