Low Expression of miR-424-3p is Highly Correlated with Clinical Failure in Prostate Cancer

E Richardsen,T Donnem,N Ness,S Andersen,M Rakaee,L T Busund,A Fassina,K A Taskén,L M Ingebriktsen,I G Mills,Y Nordby,M I Pedersen,S Al-Saad,R M Bremnes

doi:10.1038/s41598-019-47234-0

Abstract

Prostate cancer (PC) is a highly heterogenous disease and one of the leading causes of mortality in developed countries. Recently, studies have shown that expression of immune checkpoint proteins are directly or indirectly repressed by microRNAs (miRs) in many types of cancers. The great advantages of using miRs based therapy is the capacity of these short transcripts to target multiple molecules for the same- or different pathways with synergistic immune inhibition effects. miR-424 has previously been described as a biomarker of poor prognosis in different types of cancers. miR-424 is also found to target both the CTLA-4/CD80- and PD-1/PD-L1 axis. In the present study, the clinical significance of miR-424-3p expression in PC tissue was evaluated. Naïve radical prostatectomy specimens from 535 patients was used for tissue microarray construction. In situ hybridization was used to evaluate the expression of miR-424-3p and immunohistochemistry was used for CTLA-4 protein detection. In univariate- and multivariate analyses, low expression of miR-424-3p was significant associated with clinical failure-free survival, (p = 0.004) and p = 0.018 (HR:0.44, CI95% 0.22–0.87). Low expression of miR-424-3p also associated strongly with aggressive phenotype of PC. This highlight the importance of miR-424-3p as potential target for therapeutic treatment in prostate cancer.

Highlights

It has become increasingly evident that the immune system represents an important option for the development of anticancer treatment
There have been several notably immunotherapy failures in Prostate cancer (PC) and recent studies has demonstrated that the tumor microenvironment (TME) might be the reason for this because the TME might be predisposed towards immunosuppression[5,6,7,8]
We identified that low expression of the miR-424-3p was significant predictor for PC aggressiveness and outcome and was associated with aggressive features in PC; high Gleason grade group, large tumor size, perineural- and vascular infiltration

Summary

Introduction

It has become increasingly evident that the immune system represents an important option for the development of anticancer treatment. In a recent study by Xu et al in ovarian cancer cell lines and in ovarian cancer tissues, they found that the expression of miR-424 was negatively correlated with the expression level of cytotoxic T-lymphocyte associated protein 4 (CTLA-4), PD-L1 and CD80.

Results

Conclusion