CDC42-interacting protein 4 promotes metastasis of nasopharyngeal carcinoma by mediating invadopodia formation and activating EGFR signaling

Di Meng ,Xing Lv,Li Cao,Lichun Zheng ,Jing Ping Yun ,Ming Yuan Chen ,Meng Yao Wang ,Rui Sun,Hai Qiang ,Zi Meng Zhang ,Xiang Guo,Lanwei Guo ,Qiu Yan Chen ,Yan Mei,Jun Yang ,Peng Li ,Dong Hua Luo ,Bi Huang ,Yuan Yuan Qiang ,Ping Xie,Lin Wang,Chao Nan Qian

doi:10.1186/s13046-016-0483-z

Abstract

BackgroundNasopharyngeal 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.MethodsThe 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.ResultsWe 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).ConclusionWe identify the critical role of CIP4 in metastasis of NPC which suggest that CIP4 may be a potential therapeutic target of NPC patients.

Highlights

Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia
High CDC42-interacting protein 4 (CIP4) expression was significantly associated with M stage and prognosis (Table 1)
Because CDC42 interacts with neural Wiskott–Aldrich syndrome protein (N-WASP) and facilitates the nuclear translocation of epidermal growth factor receptor (EGFR) [30], we investigated the role of CIP4 EGF-induced N-WASP activation

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia. We investigated the functional and molecular mechanisms by which CDC42-interacting protein 4 (CIP4) influences NPC. Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia [1, 2]. Cells extend four different plasma membrane protrusions at the leading edge: lamellipodia, filopodia, podosomes and invadopodia [10,11,12].

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Conclusion