Xu Ming, Xie Yufeng, Sheng Weihua, Miao Jingcheng, Yang Jicheng
Department of Orthopedics, First Affiliated Hospital of Soochow University, No. 188, Shizi Road, Suzhou 215006, PR China.
Department of Oncology, First Affiliated Hospital of Soochow University, No. 188, Shizi Road, Suzhou 215006, PR China.
Technol Cancer Res Treat. 2015 Aug;14(4):369-78. doi: 10.1177/1533034614500424. Epub 2014 Oct 16.
The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential tumor-suppressive effects via multiple pathways. However, the therapeutic effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer in human osteosarcoma is still unknown. In this study, we explored the in vitro and in vivo antitumor activity of Ad-ING4 in human osteosarcoma and its potential mechanism using a MG-63 human osteosarcoma cell line. We demonstrated that Ad-ING4 induced significant growth inhibition and apoptosis, upregulated the expression of P21, P27 and Bax, downregulated the Bcl-2 expression and activated Caspase-3 in MG-63 human osteosarcoma cells. Moreover, intratumoral injections of Ad-ING4 in athymic nude mice bearing MG-63 human osteosarcoma tumors significantly suppressed osteosarcoma xenografted tumor growth, increased the expression of P21, P27 and Bax, reduced the Bcl-2 and CD34 expression and microvessel density (MVD) in tumors. This retarded MG-63 osteosarcoma growth in vitro and in vivo in an athymic nude mouse model elicited by Ad-ING4 was closely associated with the increase in the expression of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to pro-apoptotic molecules Bcl-2/Bax followed by the activation of Caspase-3 leading to apoptosis via intrinsic apoptotic pathways, and the inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 is a potential candidate for human osteosarcoma gene therapy.
生长抑制因子（ING）家族蛋白已被定义为候选肿瘤抑制因子。ING4作为ING家族的一个新成员，可通过多种途径发挥潜在的肿瘤抑制作用。然而，腺病毒介导的ING4（Ad-ING4）基因转移对人骨肉瘤的治疗效果仍不清楚。在本研究中，我们利用MG-63人骨肉瘤细胞系探讨了Ad-ING4在人骨肉瘤中的体外和体内抗肿瘤活性及其潜在机制。我们发现，Ad-ING4可诱导MG-63人骨肉瘤细胞显著生长抑制和凋亡，上调P21、P27和Bax的表达，下调Bcl-2的表达并激活Caspase-3。此外，在携带MG-63人骨肉瘤肿瘤的无胸腺裸鼠瘤内注射Ad-ING4可显著抑制骨肉瘤异种移植瘤的生长，增加P21、P27和Bax的表达，降低肿瘤中Bcl-2和CD34的表达以及微血管密度（MVD）。Ad-ING4在无胸腺裸鼠模型中体外和体内抑制MG-63骨肉瘤生长，这与细胞周期相关分子P21和P27表达增加、抗凋亡与促凋亡分子Bcl-2/Bax比值降低、随后激活Caspase-3导致通过内源性凋亡途径发生凋亡以及抑制肿瘤血管生成密切相关。因此，我们的结果表明Ad-ING4是人类骨肉瘤基因治疗的一个潜在候选者。
