尼酸腺嘌呤二核苷酸磷酸酯酶4（NOX4）是一个调节活性氧（ROS）产生的酶，在软骨肉瘤的发展中的功能还不清楚。本研究通过免疫化学检测研究了软骨肉瘤中NOX4的表达，并使用NOX4 siRNA或NOX4抑制剂GKT137831分析了NOX4在人软骨肉瘤细胞株SW1353中的活力和凋亡的作用。与癌旁组织样本相比，肿瘤中NOX4水平显著升高。NOX4的水平与患者的组织学分级和肌肉骨骼肿瘤学会分期呈正相关。SW1353中NOX4水平显著增加，与软骨细胞CHON-001相比。NOX4的沉默或GKT137831的抑制均降低了ROS的产生，并诱导了SW1353中的生长抑制和凋亡，伴随着caspase（caspase-3，caspase-8和caspase-9）的活化，Bax，细胞色素C（cyt-c），剪切的PARP的上调，以及Bcl-2的下调。此外，NOX4 siRNA和GKT137831也减少了SW1353中p-Akt，p-ERK和p-p65的表达。在体内研究中，转染NOX4 shRNA的SW1353与注射到裸鼠中的SW1353相比，显示出受损的生长能力。同时，GKT137831诱导了SW1353异种移植动物的生长抑制和凋亡，以及Bax，细胞色素C，剪切的PARP的表达增加，以及Bcl-2，p-Akt，p-ERK和p-p65的表达降低。NOX4在软骨肉瘤发展中起着积极的作用，可能成为临床上治疗软骨肉瘤的有前景的靶点。

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is an enzyme that regulates reactive oxygen species (ROS) generation, and its function in the development of chondrosarcoma remains unclear. In the present study, we studied NOX4 expression in chondrosarcoma by immunochemical examination, and analyzed the role of NOX4 in viability and apoptosis of human chondrosarcoma cell line SW1353 using NOX4 siRNA or NOX4 inhibitor GKT137831. NOX4 level significantly increased in tumor compared to that in para-carcinoma sample. The levels of NOX4 were positively correlated with histological grade and Musculoskeletal Tumor Society stage of the patients. NOX4 level was significantly increased in SW1353 compared with that in chondrocytes CHON-001. Knockdown of NOX4 or inhibition of NOX4 by GKT137831 both decreased generation of ROS, and induced growth inhibition and apoptosis in SW1353, accompanied with the activation of caspases (caspase-3, caspase-8 and caspses-9), upregulation of Bax, cytochrome C(cyt-c), cleaved-PARP and down-regulation of Bcl-2. Moreover, NOX4 siRNA and GKT137831 decreased the expression of p-Akt, p-ERK and p-p65 in SW1353 cells. In an in vivo study, NOX4 shRNA transfected SW1353 have shown impaired growth ability compared to the SW1353 when they were injected into the nude mice. Meanwhile, GKT137831 induced growth inhibition and apoptosis in SW1353 xenograft animals, together with increased expression of Bax, cyt-c, cleaved-PARP, and decreased expression of Bcl-2, p-Akt, p-ERK and p-p65. NOX4 plays a positive role in the development of chondrosarcoma and could serve as a promising target against chondrosarcoma clinically.