Jiang Xiaoxia, Wu Mengjie, Xu Zhenzhen, Wang Haohao, Wang Haiyong, Yu Xiongfei, Li Zhongqi, Teng Lisong
Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China,
Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, People's Republic of China,
Cancer Manag Res. 2018 Dec 12;10:6857-6867. doi: 10.2147/CMAR.S188364. eCollection 2018.
Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) is frequently seen in patients with gastric cancer (GC), and is generally associated with worse prognosis. HJC0152, a novel STAT3 inhibitor, has shown significant anti-tumor effects in several cancers, although its role in GC remains to be clarified.
The effect of HJC0152 on STAT3 signaling pathway and the biological behaviors of GC cells were evaluated through in vitro and/or in vivo experiments. Meanwhile, RNA sequence analysis was used to further explore its potential anti-tumor mechanisms.
HJC0152 inhibited the expression of activated STAT3 and its downstream target genes (c-Myc and clyclinD1) in GC cells, and restrained tumor growth in vivo. HJC0152 treatment induced apoptosis in the STAT3 hyper-activated AGS and MKN45 cell lines, along with down-regulation of survivin and Mcl1, and up-regulation of cleaved-poly(ADP-ribose) polymerase. Moreover, HJC0152 markedly inhibited migration and invasion of these cells. Finally, RNA sequence analysis and protein expression analyses showed that in addition to STAT3 suppression, HJC0152 also exerts its anti-tumor effects at least partly via the mitogen-activated protein kinases pathway.
Our findings highlight that HJC0152 is a promising therapeutic agent for GC.
信号转导与转录激活因子3（STAT3）的异常激活在胃癌（GC）患者中经常可见，并且通常与较差的预后相关。HJC0152是一种新型的STAT3抑制剂，尽管其在胃癌中的作用仍有待阐明，但已在多种癌症中显示出显著的抗肿瘤作用。
通过体外和/或体内实验评估HJC0152对STAT3信号通路及胃癌细胞生物学行为的影响。同时，利用RNA序列分析进一步探索其潜在的抗肿瘤机制。
HJC0152抑制胃癌细胞中活化STAT3及其下游靶基因（c-Myc和细胞周期蛋白D1）的表达，并在体内抑制肿瘤生长。HJC0152处理诱导STAT3过度激活的AGS和MKN45细胞系发生凋亡，同时下调生存素和髓细胞白血病-1（Mcl1），上调裂解的聚（ADP-核糖）聚合酶。此外，HJC0152显著抑制这些细胞的迁移和侵袭。最后，RNA序列分析和蛋白质表达分析表明，除了抑制STAT3外，HJC0152还至少部分通过丝裂原活化蛋白激酶途径发挥其抗肿瘤作用。
我们的研究结果表明HJC0152是一种有前景的胃癌治疗药物。
