Meng Dong-Fang, Xie Ping, Peng Li-Xia, Sun Rui, Luo Dong-Hua, Chen Qiu-Yan, Lv Xing, Wang Lin, Chen Ming-Yuan, Mai Hai-Qiang, Guo Ling, Guo Xiang, Zheng Li-Sheng, Cao Li, Yang Jun-Ping, Wang Meng-Yao, Mei Yan, Qiang Yuan-Yuan, Zhang Zi-Meng, Yun Jing-Ping, Huang Bi-Jun, Qian Chao-Nan
State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
J Exp Clin Cancer Res. 2017 Jan 28;36(1):21. doi: 10.1186/s13046-016-0483-z.
Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia. In this study, we investigated the functional and molecular mechanisms by which CDC42-interacting protein 4 (CIP4) influences NPC.
The expression levels of CIP4 were examined by Western blot, qRT-PCR or IHC. MTT assay was used to detect the proliferative rate of NPC cells. The invasive abilities were examined by matrigel and transwell assay. The metastatic abilities of NPC cells were revealed in BALB/c nude mice.
We report that CIP4 is required for NPC cell motility and invasion. CIP4 promotes the activation of N-WASP that controls invadopodia formation and activates EGFR signaling, which induces downstream MMP2 (matrix metalloproteinase 2) upregulation. In addition, CIP4 could promote NPC metastasis by activating the EGFR pathway. In nude mouse models, distant metastasis was significantly inhibited in CIP4-silenced groups. High CIP4 expression is an independent adverse prognostic factor of overall survival (OS) and distant metastasis-free survival (DMFS).
We identify the critical role of CIP4 in metastasis of NPC which suggest that CIP4 may be a potential therapeutic target of NPC patients.
鼻咽癌（NPC）是中国南方和东南亚地区常见的恶性肿瘤。在本研究中，我们探究了细胞分裂周期蛋白42相互作用蛋白4（CIP4）影响鼻咽癌的功能和分子机制。
采用蛋白质免疫印迹法、实时定量逆转录聚合酶链反应（qRT-PCR）或免疫组化法检测CIP4的表达水平。采用MTT法检测鼻咽癌细胞的增殖率。通过基质胶和Transwell实验检测细胞的侵袭能力。在BALB/c裸鼠体内观察鼻咽癌细胞的转移能力。
我们发现CIP4是鼻咽癌细胞迁移和侵袭所必需的。CIP4促进N-WASP的激活，N-WASP控制侵袭伪足的形成并激活表皮生长因子受体（EGFR）信号通路，进而诱导下游基质金属蛋白酶2（MMP2）的上调。此外，CIP4可通过激活EGFR信号通路促进鼻咽癌转移。在裸鼠模型中，CIP4沉默组的远处转移明显受到抑制。CIP4高表达是总生存期（OS）和无远处转移生存期（DMFS）的独立不良预后因素。
我们确定了CIP4在鼻咽癌转移中的关键作用，这表明CIP4可能是鼻咽癌患者潜在的治疗靶点。
