ROS Signaling by NOX4 Drives Fibroblast-to-Myofibroblast Differentiation in the Diseased Prostatic Stroma
ROS Signaling by NOX4 Drives Fibroblast-to-Myofibroblast Differentiation in the Diseased Prostatic Stroma
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DOI：
10.1210/me.2010-0340
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发表时间：
2011-03-01
影响因子：
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通讯作者：
Berger, Peter
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文献类型：
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作者：
Sampson, Natalie;Koziel, Rafal;Berger, Peter
基质重塑，特别是成纤维细胞向肌成纤维细胞的分化，是良性前列腺增生（BPH）和实体瘤（包括前列腺癌（PCa））的标志。 TGFβ1 局部产生的增加被认为是诱导刺激。鉴于间质重塑积极促进 BPH/PCa 的发展，人们对开发间质靶向疗法非常感兴趣。用 TGF beta 1 诱导原代人前列腺基质细胞进行成纤维细胞向肌成纤维细胞分化的微阵列和定量 PCR 分析显示，活性氧 (ROS) 产生者还原烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4 (NOX4) 上调，而含硒 ROS 清除酶下调 谷胱甘肽过氧化物酶 3、硫氧还蛋白还原酶 1 (TXNRD1) 和硒转运蛋白硒蛋白 P 血浆 1。一致地，NOX4 表达与体内肌成纤维细胞表型特异性相关，并且在人 PCa 活检的肿瘤相关基质中观察到硒蛋白 P 血浆 1 的丢失。使用慢病毒NOX4短发夹RNA介导的敲低、药理学抑制剂、抗氧化剂和硒，我们证明TGFβ1诱导NOX4衍生的ROS是TGFβ1介导的c-jun N末端激酶磷酸化所必需的，这反过来对于随后的下游细胞骨架重塑至关重要。值得注意的是，补硒通过增加 ROS 清除硒酶的生物合成来抑制分化，因为谷胱甘肽过氧化物酶 3 和 TXNRD1 表达以及 TXNRD1 酶活性得到恢复。一致地，硒耗尽会降低 NOX4 诱导下游的 ROS 水平。总的来说，这项工作表明，由 NOX4 衍生的 ROS 信号传导升高驱动的氧化还原稳态失调是患病前列腺基质中成纤维细胞向肌成纤维细胞分化的基础。此外，这些数据表明硒和/或NOX4抑制剂在预防BPH和PCa中基质细胞的功能性致病变化方面具有潜在的临床价值。 （分子内分泌学25：503-515，2011）
Stromal remodeling, in particular fibroblast-to-myofibroblast differentiation, is a hallmark of benign prostatic hyperplasia (BPH) and solid tumors, including prostate cancer (PCa). Increased local production of TGF beta 1 is considered the inducing stimulus. Given that stromal remodeling actively promotes BPH/PCa development, there is considerable interest in developing stromal-targeted therapies. Microarray and quantitative PCR analysis of primary human prostatic stromal cells induced to undergo fibroblast-to-myofibroblast differentiation with TGF beta 1 revealed up-regulation of the reactive oxygen species (ROS) producer reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and down-regulation of the selenium-containing ROS-scavenging enzymes glutathione peroxidase 3, thioredoxin reductase 1 (TXNRD1), and the selenium transporter selenoprotein P plasma 1. Consistently, NOX4 expression correlated specifically with the myofibroblast phenotype in vivo, and loss of selenoprotein P plasma 1 was observed in tumor-associated stroma of human PCa biopsies. Using lentiviral NOX4 short hairpin RNA-mediated knockdown, pharmacological inhibitors, antioxidants, and selenium, we demonstrate that TGF beta 1 induction of NOX4-derived ROS is required for TGF beta 1-mediated phosphorylation of c-jun N-terminal kinase, which in turn is essential for subsequent downstream cytoskeletal remodeling. Significantly, selenium supplementation inhibited differentiation by increasing ROS-scavenging selenoenzyme biosynthesis because glutathione peroxidase 3 and TXNRD1 expression and TXNRD1 enzyme activity were restored. Consistently, selenium depleted ROS levels downstream of NOX4 induction. Collectively, this work demonstrates that dysregulated redox homeostasis driven by elevated NOX4-derived ROS signaling underlies fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. Further, these data indicate the potential clinical value of selenium and/or NOX4 inhibitors in preventing the functional pathogenic changes of stromal cells in BPH and PCa. (Molecular Endocrinology 25: 503-515, 2011)