Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target.
Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target.
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DOI：
10.1016/j.ebiom.2020.103059
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发表时间：
2020-11
期刊：
影响因子：
11.1
通讯作者：
Garcia JGN
中科院分区：
文献类型：
--
作者：
Sun BL;Sun X;Casanova N;Garcia AN;Oita R;Algotar AM;Camp SM;Hernon VR;Gregory T;Cress AE;Garcia JGN
仍然迫切需要预防侵袭性前列腺癌（PCa）的进展。我们先前表明，分泌的细胞外烟酰胺磷酸核糖基转移酶（eNAMPT）是一种多功能的先天免疫调节剂，通过TLR4连接，这已牵连在前列腺癌的进展。在这里，我们研究了eNAMPT作为诊断生物标志物和治疗靶点在PCa进展中的作用。在具有各种PCa肿瘤阶段的人类受试者和临床随访PCa的高风险受试者中评价肿瘤NAMPT表达和血浆eNAMPT水平。利用体外和体内模型研究了PCa细胞中NAMPT表达的遗传调控以及eNAMPT在PCa侵袭中的作用。与局限于器官的PCa的最小表达相比，在人胰腺外侵袭性PCa组织中检测到显著的NAMPT表达。与男性对照组相比，PCa受试者的血浆eNAMPT水平显著升高，与器官局限性PCa受试者相比，前列腺外浸润性PCa受试者的血浆eNAMPT水平显著升高。血浆eNAMPT水平对PCa的诊断有显著的预测价值。NAMPT表达和eNAMPT分泌在人PCa细胞中高度上调，以响应缺氧诱导因子和EGF。体外细胞培养和体内临床前小鼠模型研究证实了eNAMPT介导的PCa对肌肉组织的侵袭性增强，以及每周用eNAMPT中和多克隆抗体治疗显著减弱PCa侵袭。这项研究表明，eNAMPT是PCa，特别是侵袭性PCa的潜在生物标志物。中和eNAMPT可能是预防PCa侵袭和进展的有效治疗方法。
There remains a serious need to prevent the progression of invasive prostate cancer (PCa). We previously showed that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator via TLR4 ligation which has been implicated in PCa progression. Here we investigate the role of eNAMPT as a diagnostic biomarker and therapeutic target in the progression of PCa. Tumor NAMPT expression and plasma eNAMPT level were evaluated in human subjects with various PCa tumor stages and high risk subjects followed-up clinically for PCa. The genetic regulation of NAMPT expression in PCa cells and the role of eNAMPT in PCa invasion were investigated utilizing in vitro and in vivo models. Marked NAMPT expression was detected in human extraprostatic-invasive PCa tissues compared to minimal expression of organ-confined PCa. Plasma eNAMPT levels were significantly elevated in PCa subjects compared to male controls, and significantly greater in subjects with extraprostatic-invasive PCa compared to subjects with organ-confined PCa. Plasma eNAMPT levels showed significant predictive value for diagnosing PCa. NAMPT expression and eNAMPT secretion were highly upregulated in human PCa cells in response to hypoxia-inducible factors and EGF. In vitro cell culture and in vivo preclinical mouse model studies confirmed eNAMPT-mediated enhancement of PCa invasiveness into muscle tissues and dramatic attenuation of PCa invasion by weekly treatment with an eNAMPT-neutralizing polyclonal antibody. This study suggests that eNAMPT is a potential biomarker for PCa, especially invasive PCa. Neutralization of eNAMPT may be an effective therapeutic approach to prevent PCa invasion and progression.
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影响因子：
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