Abstract A109: MicroRNA-4719 and microRNA-6756-5p correlate with aggressive prostate cancer progression in African American men through regulation of Interleukin-24
Authors: Das Dibash K. , Persaud Leah , Sauane Moira 
Published: August 2020

Prostate cancer (PCa) incidence and mortality are highest in African American men (AAM) and the molecular mechanisms underlying the racial disparities in PCa are unclear. Interleukin-24 (IL-24), a tumor suppressor whose expression is lost in most human cancers, correlates with cancer progression. Also, microRNAs (miRs) are dysregulated in cancers. microRNA target prediction algorithm tools identified miRs, miR-4719 and miR-6556-5p, as putative regulators of IL-24. This study elucidates the expression profile and role of miR-4719 and miR-6756-5p as regulators of IL-24 in PCa biology of AAM. Our work compares five different PCa cell lines: E006AA (AAM, indolent), E006AA-hT (AAM, aggressive), DU-145 (CM, aggressive), PC-3 (CM, aggressive) to a nontumorigenic prostate epithelial cell line, RWPE1 (CM). qRT-PCR analysis shows that miR-4719 and miR-6756-5p are significantly overexpressed in all PCa cell lines (by &gt;2-fold) compared to RWPE-1. Both miR-4719 (&gt;2 fold) and miR-6756-5p (&gt;50%) are higher in aggressive PCa compared to the indolent PCa, indicating their gain could be an early event in PCa progression. Moreover, miR-4719 and miR-6756-5p are significantly overexpressed in the aggressive PCa of AAM (E006AA-hT) compared to aggressive PCas for CM (PC-3 and DU-145). Interestingly, both miR-4719 and miR-6756-5p expression were higher by (&gt;3-fold) in the aggressive AAM cell line E006AA-hT compared to indolent AAM cell line- E006AA. Thus, miR-4719 and miR-6756-5p may play a role in racial disparity. Using oligonucleotide mimics and inhibitors, we evaluated the functional role of these miRs in the AAM cell lines, E006AA and E006AA-hT. MTT assays revealed that inhibition of miR-4719 and miR-6756-5p significantly decreases proliferation (&gt;40%), while overexpression of both miRs increases proliferation (&gt;20%). Inhibition of miR-4719 and miR-6756-5p further decreased the proliferation of the aggressive E006AA-hT by an extra 20%, compared to indolent E006AA. In contrast, overexpression of both miRs further increased the proliferation of E006AA-hT also by an extra 20%, compared to E006AA. Wound healing assays reveal that inhibition of miR-4719 and miR-6756-5p reduced migration by ~50% compared to the negative control (NC). Strikingly, overexpression of both miRs increased migration by at least 2- and 4-fold, respectively. We observed that IL-24 was downregulated in all PCa cells compared to RWPE-1, suggesting a possible role of these miRs in suppressing IL-24. qRT-PCR analysis show inhibition of miR-4719 and miR-6756-5p significantly increases the expression of IL-24 (by ~2-fold) in PCa cells compared to the NC. In contrast, overexpression of both miRs reduces the expression of IL-24. Our findings indicate that miR-4719 and miR-6756-5p may regulate IL-24 expression and may be biomarkers that can differentiate between indolent and aggressive PCa in AAM. Strategies to inhibit miR-4719 and miR-6756-5p expression to increase IL-24 in PCa could have therapeutic efficacy in AAM.

Citation Format: Dibash K. Das, Leah Persaud, Moira Sauane. MicroRNA-4719 and microRNA-6756-5p correlate with aggressive prostate cancer progression in African American men through regulation of Interleukin-24 [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A109.