Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Endocr Relat Cancer. 2023 Jun 26;30(8). doi: 10.1530/ERC-22-0247. Print 2023 Aug 1.
Prostate cancer (PCa) is the second-most common cause of male cancer-related death in western industrialized countries, and the emergence of metastases is a key challenge in the treatment of PCa. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play an important role in the regulation of diverse cellular and molecular processes during the development and progression of cancer. Here, we utilized a unique cohort of castration-resistant prostate cancer metastases (mCRPC) and corresponding localized tumors and RNA sequencing (RNA-seq). First, we showed that patient-to-patient variability accounted for most of the variance in lncRNA expression between the samples, suggesting that genomic alterations in the samples are the main drivers of lncRNA expression in PCa metastasis. Subsequently, we identified 27 lncRNAs with differential expression (DE-lncRNAs) between metastases and corresponding primary tumors, suggesting that they are mCRPC-specific lncRNAs. Analyses of potential regulation by transcription factors (TFs) revealed that approximately half of the DE-lncRNAs have at least one binding site for the androgen receptor in their regulatory regions. In addition, TF enrichment analysis revealed the enrichment of binding sites for PCa-associated TFs, such as FOXA1 and HOXB13, in the regulatory regions of the DE-lncRNAs. In a cohort of prostatectomy-treated prostate tumors, four of the DE-lncRNAs showed association with progression-free time and two of them (lnc-SCFD2-2 and lnc-R3HCC1L-8) were independent prognostic markers. Our study highlights several mCRPC-specific lncRNAs that might be important in the progression of the disease to the metastatic stage and may also serve as potential biomarkers for aggressive PCa.
前列腺癌（PCa）是西方工业化国家男性癌症相关死亡的第二大主要原因，而转移的出现是 PCa 治疗的关键挑战。越来越多的研究表明，长链非编码 RNA（lncRNA）在癌症发生和发展过程中对多种细胞和分子过程的调节中发挥着重要作用。在这里，我们利用一组独特的去势抵抗性前列腺癌转移（mCRPC）和相应的局部肿瘤和 RNA 测序（RNA-seq）进行研究。首先，我们表明患者间的变异性解释了样本之间 lncRNA 表达的大部分差异，这表明样本中的基因组改变是 PCa 转移中 lncRNA 表达的主要驱动因素。随后，我们鉴定了 27 个在转移和相应的原发性肿瘤之间表达差异的 lncRNA（DE-lncRNA），这表明它们是 mCRPC 特异性的 lncRNA。对转录因子（TF）潜在调控的分析表明，大约一半的 DE-lncRNA 在其调控区域至少有一个雄激素受体的结合位点。此外，TF 富集分析揭示了 DE-lncRNA 调控区域中与 PCa 相关的 TF（如 FOXA1 和 HOXB13）结合位点的富集。在一组接受前列腺切除术治疗的前列腺肿瘤中，四个 DE-lncRNA 与无进展时间相关，其中两个（lnc-SCFD2-2 和 lnc-R3HCC1L-8）是独立的预后标志物。我们的研究强调了几个 mCRPC 特异性 lncRNA，它们可能在疾病进展到转移阶段中很重要，并且也可能作为侵袭性 PCa 的潜在生物标志物。
