The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy
The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy
复制标题
TRIP4 在黑色素瘤进展中的促肿瘤作用及其对 BRAF 靶向治疗反应的影响
DOI：
10.1016/j.jid.2017.07.850
复制
发表时间：
2018-01-01
影响因子：
6.5
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
--
作者：
Hao, Jiaojiao;Xu, Hua;Deng, Wuguo
基于小干扰RNA文库筛选，TRIP 4被鉴定为在黑素瘤细胞中具有增殖促进作用，然而，其在黑素瘤进展中的精确功能完全未知。在这里，我们探讨了TRIP 4在黑色素瘤中的致癌作用。TRIP 4在人黑色素瘤细胞和组织中观察到高表达。它的敲低在体外和体内抑制黑色素瘤的进展，包括黑色素瘤细胞增殖，迁移，侵袭抑制和凋亡诱导。进一步的机制分析表明，TRIP 4通过调节考克斯-2和iNOS表达促进黑色素瘤生长，部分通过间接激活NF-κ B信号传导，部分通过与p300协同作用将其自身直接锚定在考克斯-2和iNOS启动子。TRIP 4被证实调节BRAF突变的人黑素瘤细胞和异种移植物中对抗BRAF靶向剂的敏感性。此外，临床数据显示TRIP 4的高表达与考克斯-2和iNOS的表达增加正相关，并预测100例黑色素瘤患者的预后不良。总的来说，这些结果显示了TRIP 4的促肿瘤发生作用，提供了对TRIP 4作为候选治疗靶标的机制的深入了解，并表明TRIP 4和BRAF双重靶向作为黑色素瘤的有效治疗策略的潜力。
TRIP4 was identified as having a proliferation promoting effect in melanoma cells based on small interfering RNA library screening, however, its precise function in melanoma progression is completely unknown. Here, we explored the carcinogenic role of TRIP4 in melanoma. The high expression of TRIP4 was observed in human melanoma cells and tissues. Its knockdown suppressed melanoma progression in vitro and in vivo, including melanoma cell proliferation, migration, and invasion inhibition and apoptosis induction. Further mechanistic analysis showed that TRIP4 promoted melanoma growth through modulation of COX-2 and iNOS expression partially by activating NF-kappa B signaling indirectly and partially by the direct anchoring of itself at COX-2 and iNOS promoter via synergy with p300. TRIP4 was confirmed to regulate the sensitivity to anti-BRAF targeted agents in BRAF-mutant human melanoma cells and xenografts. In addition, clinical data showed that high expression of TRIP4 was positively correlated with increased expression of COX-2 and iNOS and predicted poor prognosis in a cohort of 100 melanoma patients. Collectively, these results show a pro-tumorigenic role of TRIP4, provide an insight into the mechanism of TRIP4 as a candidate therapeutic target, and suggest the potential of TRIP4 and BRAF dual targeting as an effective therapeutic strategy for melanoma.