Institute of Anatomy and Experimental Morphology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.
SRC Bioclinicum, Ugreshskaya str 2/85, Moscow, Russia.
Eur J Cancer. 2020 Sep;137:93-107. doi: 10.1016/j.ejca.2020.06.025. Epub 2020 Aug 1.
Distant metastasis formation is the major clinical problem in prostate cancer (PCa) and the underlying mechanisms remain poorly understood. Our aim was to identify novel molecules that functionally contribute to human PCa systemic dissemination based on unbiased approaches.
We compared mRNA, microRNA (miR) and protein expression levels in established human PCa xenograft tumours with high (PC-3), moderate (VCaP) or weak (DU-145) spontaneous micrometastatic potential. By focussing on those mRNAs, miRs and proteins that were differentially regulated among the xenograft groups and known to interact with each other we constructed dissemination-related mRNA/miR and protein/miR networks. Next, we clinically and functionally validated our findings.
Besides known determinants of PCa progression and/or metastasis, our interaction networks include several novel candidates. We observed a clear role of epithelial-to-mesenchymal transition (EMT) pathways for PCa dissemination, which was additionally confirmed by an independent human PCa model (ARCAP-E/-M). Two converging nodes, CD46 (decreasing with metastatic potential) and DDX21 (increasing with metastatic potential), were used to test the clinical relevance of the networks. Intriguingly, both network nodes consistently added prognostic information for patients with PCa whereas CD46 loss predicted poor outcome independent of established parameters. Accordingly, depletion of CD46 in weakly metastatic PCa cells induced EMT-like properties in vitro and spontaneous micrometastasis formation in vivo.
The clinical and functional relevance of the dissemination-related interaction networks shown here could be successfully validated by proof-of-principle experiments. Therefore, we suggest a direct pro-metastatic, clinically relevant role for the multiple novel candidates included in this study; these should be further exploited by future studies.
远处转移的形成是前列腺癌（PCa）的主要临床问题，其潜在机制仍知之甚少。我们的目的是基于无偏方法鉴定新的分子，这些分子在功能上有助于人类 PCa 的全身扩散。
我们比较了具有高（PC-3）、中（VCaP）或弱（DU-145）自发微转移潜能的已建立的人 PCa 异种移植肿瘤中的 mRNA、microRNA（miR）和蛋白质表达水平。通过关注那些在异种移植组中差异调节且已知相互作用的 mRNAs、miRs 和蛋白质，我们构建了与扩散相关的 mRNA/miR 和蛋白质/miR 网络。接下来，我们对这些发现进行了临床和功能验证。
除了已知的 PCa 进展和/或转移决定因素外，我们的相互作用网络还包括几个新的候选者。我们观察到上皮-间充质转化（EMT）途径对 PCa 扩散的明显作用，这一作用通过另一个独立的人 PCa 模型（ARCAP-E/-M）得到了进一步证实。两个收敛节点，CD46（随着转移潜能的降低而减少）和 DDX21（随着转移潜能的增加而增加），用于测试网络的临床相关性。有趣的是，两个网络节点都一致地为 PCa 患者提供了预后信息，而 CD46 的缺失独立于既定参数预测了不良结局。因此，在弱转移性 PCa 细胞中耗尽 CD46 在体外诱导 EMT 样特性，并在体内自发形成微转移。
通过原理验证实验，成功验证了所显示的与扩散相关的相互作用网络的临床和功能相关性。因此，我们建议在本研究中包括的多个新候选者具有直接的促转移、临床相关作用；这些候选者应在未来的研究中进一步探索。
