The Role of lncRNAs TAPIR-1 and -2 as Diagnostic Markers and Potential Therapeutic Targets in Prostate Cancer.

M Friedrich ,Achim Aigner,Kristin Reiche,Kurt Engeland,Michael H Muders,Gabriele Pfeifer,Karolin Wiedemann,Friedemann Horn,Anna Dubrovska,Sven-Holger Puppel,Jörg Hackermüller,Ulrike Köhl,Michael Rade,Ivonne Zipfel,Claudia Peitzsch,Ulrich Sommer,Sabina Christ,Jörg Lehmann,S Schreiber ,Gustavo Baretton ,Marieta Toma ,M Fröhner ,Stefanie Petrou Binder ,G Müller ,Manfred P Wirth ,S Füssel

doi:10.3390/cancers12051122

Abstract

In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa.

Highlights

Prostate cancer (PCa) is the most commonly diagnosed cancer in men world-wide
Data are shown as means ± s.d.; significance p ≤ 0.001 (***), ns = non-significant; two-sided student-t test. (C) Western blot analyses of different proteins 72 h post transfection with siRNAs directed against TAPIR-1, p53, and p21CIP1 /CDKN1A are shown. β-actin served as loading control
The area under the curve (AUC) value from the prostate specific antigen blood test (PSA; a clinical protein marker used for prostate cancer (PCa) screening) in our cohort is only 0.84, while that of protein marker used for PCa screening) in our cohort is only 0.84, while that of TAPIR-1 and -2 obtained from tissue specimens amounts to ~0.94

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed cancer in men world-wide. The present standard protein-based prostate specific antigen (PSA) screening test is being disputed due to a high rate of false positive findings [1,2,3]. Better marker candidates need to be found. The management of PCa comprises potentially curative treatment using radical prostatectomy as well as radiation and hormone deprivation therapy [4]. Depending on the tumor stage, over 55% of the PCa can be permanently controlled using radiation therapy [5,6,7].

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Discussion

Conclusion