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EGF upregulates Na + /H + exchanger NHE1 by post‐translational regulation that is important for cervical cancer cell invasiveness
Author(s) -
Chiang Yihan,
Chou ChengYang,
Hsu KengFu,
Huang YuFang,
Shen MengRu
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21277
Subject(s) - cervical cancer , cancer , chemistry , cancer research , microbiology and biotechnology , biology , genetics
Na + /H + exchanger 1 (NHE1) is involved in cell migration but little is known about the signal pathways that regulate NHE1 activity and that are associated with tumor cell invasiveness. This study is to investigate the mechanisms by which epidermal growth factor (EGF) regulates NHE1 expression to promote cervical cancer cell invasiveness and the clinical significance in early‐stage cervical cancer. NHE1 protein was scanty in normal or noncancerous cervical tissues of all surgical specimens examined (n = 92). Tumor tissues clearly expressed NHE1 protein with different amounts. The differential expression level of NHE1 is associated with the clinical outcome. NHE1 protein was also differentially expressed between normal cervical epithelial cells and two cervical cancer cell lines. Cervical cancer cells benefit some enhanced cellular functions from NHE1 abundance, such as cell volume regulation, migration, and invasion. Interestingly, NHE1 colocalized with EGF in cervical cancer tissues. Studies in cell culture systems indicated that EGF‐stimulated NHE1 abundance in a time‐dependent manner by post‐translational regulation. This implies a likely autocrine or paracrine EGF stimulation of NHE1 production in vivo. In addition, the phosphoinositide 3‐kinase pathway is the dominant signal controlling EGF‐stimulated NHE1 abundance. Pharmacological inhibition of NHE1 activity markedly inhibited the basal and EGF‐stimulated cervical cancer cell migration. Image studies and immunoprecipitaion experiments suggest that EGF‐induced NHE1 translocation to the leading‐edge lamellipodia, where NHE1 interacted with actin‐associated protein Ezrin, thereby remodeling cytoskeleton and stimulating cervical cancer cell migration. In conclusion, EGF upregulates NHE1 by post‐translational regulation that is important for cervical cancer cell invasiveness. J. Cell. Physiol. 214: 810–819, 2008. © 2007 Wiley‐Liss, Inc.