Friedrich Maik, Wiedemann Karolin, Reiche Kristin, Puppel Sven-Holger, Pfeifer Gabriele, Zipfel Ivonne, Binder Stefanie, Köhl Ulrike, Müller Gerd A, Engeland Kurt, Aigner Achim, Füssel Susanne, Fröhner Michael, Peitzsch Claudia, Dubrovska Anna, Rade Michael, Christ Sabina, Schreiber Stephan, Hackermüller Jörg, Lehmann Jörg, Toma Marieta I, Muders Michael H, Sommer Ulrich, Baretton Gustavo B, Wirth Manfred, Horn Friedemann
Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Johannisallee 30, D-04103 Leipzig, Germany.
Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology, RIBOLUTION Biomarker Center Perlickstr. 1, D-04103 Leipzig, Germany.
Cancers (Basel). 2020 Apr 30;12(5):1122. doi: 10.3390/cancers12051122.
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 ( and . 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 -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 significantly reduced tumor growth. These findings point to a crucial role of and in PCa.
为寻找适用于前列腺癌诊断和治疗的新型生物标志物，我们对40例前列腺癌（PCa）患者和8例良性前列腺增生患者的组织标本进行了全基因组转录组测序。我们鉴定出两个紧密相邻的基因间长链非编码转录本，它们在PCa中高表达。对包含155例患者的更大队列进行的微阵列研究显示，这些转录本具有强大的诊断潜力（AUC~0.94），我们将其命名为肿瘤相关前列腺癌上调lncRNA（和）。为测试它们的治疗潜力，我们进行了siRNA敲低实验。敲低导致p53/TP53肿瘤抑制蛋白水平升高，随后大量细胞周期和损伤修复关键调节因子下调。此外，在放疗抗性肿瘤细胞中，敲低导致这些细胞对放疗重新敏感。因此，在小鼠的临床前PCa异种移植模型中，全身应用负载靶向的siRNA的纳米颗粒显著降低了肿瘤生长。这些发现表明和在PCa中起关键作用。
