Abstract 1165: PKC epsilon modulated miRNAs profiling during development of prostate cancer in transgenic adenocarcinoma of mouse prostate model

Abstract

Abstract MicroRNAs (miRNAs) are small nucleotides endogenously expressed non-coding RNAs that have been implicated in a wide range of cellular processes. Dysregulation of miRNA expression has been identified in a number of cancers including prostate. Evidence indicates that miRNAs are involved in prostate cancer (PCa) development and metastasis via activating several oncogenes and inhibiting tumor suppressor genes. However, the molecules’ targeting these microRNAs is poorly understood. Protein kinase C epsilon (PKC∈), a novel PKC isoforms, is over-expressed in both human and mouse PCa. We have previously shown that PKC∈ expression correlates with the aggressiveness of PCa. We generated PKC∈-deleted TRAMP mice by crossbreeding transgenic adenocarcinoma of mouse prostate (TRAMP) (TG//WT) mice with PKC∈ knock out (TG//KO) mice. Sixteen weeks old TG Wild-type (TG//WT), TG//PKC∈ Heterozygous (TG//Het) and TG//PKC∈ KO (TG//KO) mice were evaluated for PCa development and metastasis. We observed that deletion of PKC∈ in TRAMP mice inhibited PCa development and metastasis as observed by CT-PET scanning, tumor weight and histopathology of livers, lungs, kidneys and lymph nodes. To determine the clues about the miRNAs, which are modulated by PKC∈, we performed global miRNA profiling in prostate tissues of TG//WT and TG//KO mice by using miRNA Microarray chip containing transcripts of 750 miRNAs (Listed in Sanger miRBase Release 15.0). We observed a significant down-regulation of 7 miRNAs (miRNA762, miR125b-5p, miR-16, miR-467a-1, miR-574-3p, miRNA-451 and miR-669f) and up-regulation of 6 miRNAs (miR-1187, miR-1195, miR-2133, miR-574-5p, miR-690 and miR-709) in prostate tissues of TG//KO mice compared to TG//WT mice. It has been reported that miRNA-451 plays a role in the induction of mTOR signaling, which is well documented for its role in human PCa progression. Importantly, we observed 20-fold decreased expression of miRNA-451 in prostate tissues of TG//KO mice compared to TG//WT mice. It has been reported that up-regulation of miRNA-709 inhibits expression of BORIS, a tumor promoting transcription factor. We observed two fold induction of miRNA-709 in TG//KO mice. Taken together these finding suggest that PKC∈ plays an important role in PCa development and metastasis via up-regulating oncogenic miRNA and down regulating tumor suppressing miRNA. We suggest that these miRNAs modulated by PKC∈ have role in PCa development and metastasis. However further studies warranted to understand the functional implication of these miRNAs in human PCa. (Support: NIH Grant, CA35368). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1165. doi:10.1158/1538-7445.AM2011-1165