Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.
Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.
复制标题
DOI：
10.1038/onc.2016.482
复制
发表时间：
2017-06-15
期刊：
影响因子：
8
通讯作者：
Hollier BG
中科院分区：
文献类型：
--
作者：
Tse BWC;Volpert M;Ratther E;Stylianou N;Nouri M;McGowan K;Lehman ML;McPherson SJ;Roshan-Moniri M;Butler MS;Caradec J;Gregory-Evans CY;McGovern J;Das R;Takhar M;Erho N;Alshalafa M;Davicioni E;Schaeffer EM;Jenkins RB;Ross AE;Karnes RJ;Den RB;Fazli L;Gregory PA;Gleave ME;Williams ED;Rennie PS;Buttyan R;Gunter JH;Selth LA;Russell PJ;Nelson CC;Hollier BG
最近的证据表明跨膜辅助受体神经毡蛋白-1 (NRP1) 与癌症进展有关。 NRP1 主要作为神经元引导和血管生成的调节因子，也在多种人类恶性肿瘤中表达，促进肿瘤血管生成。然而，NRP1 在肿瘤进展中的非血管生成作用仍知之甚少。在这项研究中，我们将NRP1定义为一种雄激素抑制基因，其表达在前列腺肿瘤适应雄激素靶向治疗（ATT）以及随后进展为转移性去势抵抗性前列腺癌（mCRPC）的过程中升高。利用短发夹 RNA (shRNA) 介导的 NRP1 抑制，我们证明 NRP1 调节 mCRPC 细胞模型的间充质表型以及体内肿瘤细胞的侵袭性和转移性播散。在患者中，组织微阵列的免疫组织化学染色和 mRNA 表达分析显示，NRP1 表达与 Gleason 分级、病理 T 评分、阳性淋巴结状态和主要治疗失败的增加之间呈正相关。此外，对几个大型临床前列腺癌（PCa）队列的多变量分析确定，根治性前列腺切除术中的 NRP1 表达是放射治疗后生化复发、转移和癌症特异性死亡率的独立预后生物标志物。这项研究首次将 NRP1 确定为一种新型雄激素抑制基因，在前列腺肿瘤对 ATT 的适应性反应过程中上调，也是临床转移和致命性 PCa 的预后生物标志物。
Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.