Sattari Mina, Rauhala Hanna, Latonen Leena, Isaacs William B, Nykter Matti, Bova G Steven, Kesseli Juha, Visakorpi Tapio
Endocr Relat Cancer. 2025 Jun 26;32(7). doi: 10.1530/ERC-25-0070. Print 2025 Jul 1.
Prostate cancer (PCa) is a significant cause of male mortality worldwide. Since metastases are the underlying cause of lethality, identifying markers for metastatic potential would be highly valuable. To address this issue, we set out to identify protein-coding genes with metastasis-specific expression changes in PCa. We employed a previously reported unique cohort consisting of metastases from castration-resistant prostate cancer (mCRPC) and matching primary tumors. Our comprehensive gene expression analyses identified 85 differentially expressed genes (DEGs) associated specifically with mCRPC, comprising 63 upregulated and 22 downregulated genes. Investigation of the transcription factors (TFs), such as the androgen receptor and its co-regulators FOXA1 and HOXB13, known to be important in prostate tumorigenesis, revealed their involvement in the differential expression of these genes. Furthermore, we identified enriched binding sites for nine TFs, namely EZH2, SUZ12, TLE3, TP63, CBX7, RNF2, SP140, JARID2, and CBX8, in the regulatory regions of the DEGs. Analysis of progression-free survival of prostatectomy-treated men highlighted 16 DEGs with significant prognostic value. Of these, three genes (FRMPD1, TMEM18, and ZNHIT3) were independent prognostic markers of biochemical recurrence. TMEM18 has putative androgen receptor-binding sites in its promoter region, and analysis of LNCaP cells following stimulation with dihydrotestosterone revealed a significant upregulation of TMEM18, confirming the androgen regulation of the gene. Furthermore, we confirmed the prognostic significance of TMEM18 expression at the protein level with immunohistochemistry (IHC) in a primary PCa tumor cohort. In conclusion, we identified 85 mCRPC-associated genes and showed that TMEM18 has prognostic value in early PCa.
前列腺癌（PCa）是全球男性死亡的重要原因。由于转移是致死的根本原因，因此识别具有转移潜能的标志物将具有极高的价值。为解决这一问题，我们着手鉴定在PCa中具有转移特异性表达变化的蛋白质编码基因。我们采用了先前报道的一个独特队列，该队列由去势抵抗性前列腺癌（mCRPC）转移灶及配对的原发性肿瘤组成。我们全面的基因表达分析鉴定出85个与mCRPC特异性相关的差异表达基因（DEG），其中包括63个上调基因和22个下调基因。对已知在前列腺肿瘤发生中起重要作用的转录因子（TF），如雄激素受体及其共调节因子FOXA1和HOXB13进行研究，发现它们参与了这些基因的差异表达。此外，我们在DEG的调控区域中鉴定出9个TF（即EZH2、SUZ12、TLE3、TP63、CBX7、RNF2、SP140、JARID2和CBX8）的富集结合位点。对接受前列腺切除术治疗的男性的无进展生存期分析突出显示了16个具有显著预后价值的DEG。其中，三个基因（FRMPD1、TMEM18和ZNHIT3）是生化复发的独立预后标志物。TMEM18在其启动子区域具有假定的雄激素受体结合位点，用二氢睾酮刺激LNCaP细胞后的分析显示TMEM18显著上调，证实了该基因受雄激素调控。此外，我们通过免疫组织化学（IHC）在原发性PCa肿瘤队列中证实了TMEM18蛋白水平表达的预后意义。总之，我们鉴定出85个与mCRPC相关的基因，并表明TMEM18在早期PCa中具有预后价值。
