Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Cancer Epidemiol Biomarkers Prev. 2017 Dec;26(12):1781-1787. doi: 10.1158/1055-9965.EPI-17-0453. Epub 2017 Sep 22.
Recent data suggest that neuroendocrine signaling pathways may play a role in the progression of prostate cancer, particularly for early-stage disease. We aimed to explore whether expression of selected genes in the adrenergic, serotoninergic, glucocorticoid, and dopaminergic pathways differs in prostate tumor tissue from men with lethal disease compared with men with nonlethal disease. On the basis of the Swedish Watchful Waiting Cohort, we included 511 men diagnosed with incidental prostate cancer through transurethral resection of the prostate during 1977-1998 with follow-up up to 30 years. For those with tumor tissue ( = 262), we measured mRNA expression of 223 selected genes included in neuroendocrine pathways. Using DNA from normal prostate tissue ( = 396), we genotyped 36 SNPs from 14 receptor genes. Lethal prostate cancer was the primary outcome in analyses with pathway gene expression and genetic variants. Differential expression of genes in the serotoninergic pathway was associated with risk of lethal prostate cancer ( = 0.007); similar but weaker associations were noted for the adrenergic ( = 0.014) and glucocorticoid ( = 0.020) pathways. Variants of the (rs2296972; = 0.002) and (rs33388; = 0.035) genes (within the serotoninergic and glucocorticoid pathways) were associated with lethal cancer in overdominant models. These genetic variants were correlated with expression of several genes in corresponding pathways ( < 0.05). Our findings lend support to hypothesis that the neuroendocrine pathways, particularly serotoninergic pathway, are associated with lethal outcome in the natural course of localized prostate cancer. This study provides evidence of the role of neuroendocrine pathways in prostate cancer progression that may have clinical utility. .
最近的数据表明，神经内分泌信号通路可能在前列腺癌的进展中发挥作用，特别是对于早期疾病。我们旨在探索在具有致命性疾病的男性与具有非致命性疾病的男性的前列腺肿瘤组织中，肾上腺素能、血清素能、糖皮质激素和多巴胺能途径中选定基因的表达是否不同。基于瑞典观察等待队列，我们纳入了 511 名通过经尿道前列腺切除术在 1977 年至 1998 年期间偶然诊断出前列腺癌的男性，随访时间长达 30 年。对于那些有肿瘤组织的男性（=262），我们测量了 223 个选定基因的信使 RNA 表达，这些基因包括神经内分泌途径中的基因。利用来自正常前列腺组织的 DNA（=396），我们对来自 14 个受体基因的 36 个单核苷酸多态性进行了基因分型。致命性前列腺癌是分析中神经内分泌途径基因表达和遗传变异的主要结果。血清素能途径中基因的差异表达与致命性前列腺癌的风险相关（=0.007）；在肾上腺素能途径（=0.014）和糖皮质激素途径（=0.020）中也观察到类似但较弱的关联。基因（rs2296972；=0.002）和基因（rs33388；=0.035）的变体（位于血清素能和糖皮质激素途径内）在超显性模型中与致命性癌症相关。这些遗传变异与相应途径中几个基因的表达相关（<0.05）。我们的发现支持这样一种假说，即神经内分泌途径，特别是血清素能途径，与局限性前列腺癌自然病程中的致命结局有关。这项研究提供了神经内分泌途径在前列腺癌进展中的作用的证据，这可能具有临床应用价值。
