miR-30e* is overexpressed in prostate cancer and promotes NF-κB-mediated proliferation and tumor growth

Abstract

// Shawn M. Egan 1 , Ellen Karasik 2 , Leigh Ellis 3 and Sandra O. Gollnick 4 1 Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA 2 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA 3 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 4 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA Correspondence to: Sandra O. Gollnick, email: Sandra.gollnick@roswellpark.org Keywords: NF-κB, microRNA, prostate cancer, cyclin D1 Received: December 30, 2015      Accepted: June 02, 2017      Published: June 28, 2017 ABSTRACT According to the CDC prostate cancer (CaP) has the highest incidence and second highest mortality rate amongst cancers in American men. Constitutive NF-κB activation is a hallmark of CaP and this pathway drives many pro-tumorigenic characteristics of CaP cells, including cell proliferation and survival. An activated NF-κB gene signature is predictive of CaP progression and biochemical recurrence following therapeutic intervention. However, the mechanisms that perpetuate NF-κB activation are incompletely understood. Genes that control NF-κB activity are rarely mutated in CaP suggesting that epigenetic mechanisms may contribute to constitutive NF-κB activation. microRNAs (miRs) epigenetically regulate many genes involved with NF-κB activation. IκBα is a direct inhibitor of NF-κB; it binds to and sequesters NF-κB in the cytoplasm resulting in functional inhibition. IκBα is a target gene of miR-30e* yet the expression and oncological impact of miR-30e* in CaP is unknown. We report that miR-30e* expression is elevated in multiple murine models of CaP and is most pronounced in late stage disease. miR-30e* drives CaP proliferation and tumor growth through inhibition of IκBα, which results in chronic activation of NF-κB. Additionally, we show that inhibition of miR-30e* improves chemotherapeutic control of CaP. Thus, miR-30e* may prove to be a novel clinical target whose inhibition leads to decreased CaP cell proliferation and sensitization of CaP cells to chemotherapeutics.