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  • Title: [Effect of AG490 on JAK2/STAT3 signaling pathway in human retinoblastoma HXO-RB44 cell lines].
    Author: Xu B, Chen X, Tan J, Xu X.
    Journal: Zhong Nan Da Xue Xue Bao Yi Xue Ban; 2018 Oct 28; 43(10):1061-1067. PubMed ID: 30523225.
    Abstract:
    To investigate the role of Janus kinase (JAK) inhibitor AG490 in the anti-proliferation and cell cycle in human retinoblastoma HXO-RB44 cell lines in vitro, and to explore its effect on the expression of JAK2/signal transducer and activator of transcription 3 (STAT3).
 Methods: Cells were divided into an experiment group and a control group, and the experiment group was further divided into 6 sub-groups according to different AG490 concentrations (6.25, 12.50, 25.00, 50.00 or 100.00 μmol/L). Cell proliferation in the different groups was analyzed by cell vitality determination. Cell cycle distribution and apoptosis rate were examined by flow cytometry. The protein levels of STAT3, p-STAT3 and vascular endothelial growth factor (VEGF) were detected by Western blot.
 Results: After 48 h treatment with AG490, the viability of HXO-RB44 cells was reduced in a concentration-dependent manner. Compared with the control group, there was no significant difference in the experiment groups except the 6.25 μmol/L group (all P>0.05). The apoptosis rates in the experiment groups were significantly increased with increase in concentration of AG490 compared with that in the control group (all P<0.05). The cell ratio in the G1 phase in 50 or 100 μmol/L group was increased, whereas the cell ratio in the S phase was decreased. Western blot results showed that the expressions of STAT3 and p-STAT3 in the experiment groups were dramatically reduced with the increase in concentration of AG490 compared with that in the control group (all P<0.05). VEGF expression didn't obviously change in the experiment groups with AG490 concentration less than 12.5 μmol/L compared with that in the control group (both P>0.05), but there were significant differences in the other experiment groups (all P<0.05). 
 Conclusion: JAK inhibitor AG490 can inhibit proliferation and promote apoptosis of the retinoblastoma HXO-RB44 cells through down-regulation of JAK2/STAT3 signaling pathway. 目的：研究Janus激酶(Janus kinase，JAK)抑制剂AG490对人视网膜母细胞瘤HXO-RB44细胞株体外抗增殖及细胞周期的作用，探讨其对JAK2/信号转导与转录激活因子3(signal transducer and activator of transcription 3，STAT3)信号通路蛋白表达的影响。方法：本实验分为实验组和对照组，实验组又根据不同浓度(6.25，12.50，25.00，50.00，100.00，200.00 μmol/L)的AG490处理分为6个不同浓度的实验组。采用细胞的活力测定法检测各组细胞增殖状态。应用流式细胞术对各组中细胞凋亡及周期进行分析。采用Western印迹检测处理后STAT3，p-STAT3及血管内皮生长因子(vascular endothelial growth factor，VEGF)蛋白的表达。结果：AG490处理HXO-RB44细胞株48 h后，随着药物浓度的增加，细胞抑制率增加，细胞存活率下降(均P<0.05)。除6.25 μmol/L实验组外，其余5组与对照组两两比较，差异均有统计学意义(均P<0.05)。流式细胞术显示：随着AG490药物浓度的增加，细胞凋亡率呈逐渐增高趋势，与对照组相比，差异均有统计学意义(均P<0.05)。其中，50.00和100.00 μmol/L实验组G1期细胞比例显著增多，相应地处于S期的细胞比例减少。Western 印迹显示：随着AG490药物浓度的增加，STAT3和p-STAT3蛋白的表达量逐渐下降，与对照组相比，差异均有统计学意义(均P<0.05)；VEGF表达量逐渐下降，与对照组相比，6.25和12.50 μmol/L实验组的VEGF差异均无统计学意义(均P>0.05)，其余各实验组差异均有统计学意义(均P<0.05)。结论：JAK抑制剂AG490能抑制HXO-RB44细胞株生长及增殖，促进细胞的凋亡增加；并通过阻断JAK2/STAT3信号通路而下调STAT3，p-STAT3和VEGF的表达，从而抑制HXO-RB44细胞株的增殖，加速其凋亡。.
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