Abstract
NEDD9, a focal adhesion scaffolding protein, has been recently proposed to regulate invasion and metastasis in some cancer types, but unknown in cervical cancer. The aim of this study was to determine if NEDD9 was involved in the progression and metastasis of cervical cancer. The experimental results showed NEDD9 protein was overexpressed in cervical cancer compared with normal cervical epithelium tissues. Overexpression of NEDD9 was correlated with histological grading, lymph node metastasis, and FIGO stage of cervical cancer. Silencing NEDD9 resulted in tyrosine dephosphorylation of FAK and SRC oncoproteins, and decreased cell migration and invasion in the cervical carcinoma SiHa and HeLa cells. Overexpression of NEDD9 led to tyrosine phosphorylation of FAK and SRC oncoproteins, and increased cell migration and invasion. Moreover, tyrosine phosphorylation of NEDD9 was significantly decreased via suppressing tyrosine phosphorylation of FAK or SRC, suggesting a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC. In addition, our data showed that silencing NEDD9 decreased Vimentin expression and increased E-cadherin expression in cervical cancer cells, and vice versa. E-cadherin was subject to regulation of NEDD9, FAK and SRC, but altered neither tyrosine-phosphorylated nor total NEDD9. Our findings suggest that NEDD9 is overexpressed in cervical cancer tissues and cells, and overexpressed NEDD9 promotes migration and invasion in cervical carcinoma cells, probably via a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC.
Highlights
Cervical cancer is the third most commonly diagnosed cancer in women worldwide, especially in developing countries
We found that NEDD9 protein was overexpressed in most cervical carcinoma tissues but poorly expressed in normal cervical epithelium tissues (Figure 1A)
NEDD9 was initially first identified as one of new genes expressed by neural precursor cells but down-regulated following fetal development [3], several current studies found that NEDD9 overexpression, as oncogenic signaling abnormalities, was associated with cancer metastasis in breast cancer [6,20,21], glioblastoma [9], melanoma [10] and head and neck squamous cell carcinoma (HNSCC) [13], as well as linked to drug resistance in gastrointestinal stromal tumor (GIST) [22]
Summary
Cervical cancer is the third most commonly diagnosed cancer in women worldwide, especially in developing countries. Surgery is only suitable for early stage diseases and radiotherapy results in undesirable side effects, such as ovarian failure, vaginal stenosis, radiocystitis and radiation proctitis which influence the quality of the patient’s life [2] These facts underscore an urgent need for the development of more effective and novel therapeutic targets. NEDD9 gene, first identified in neuronal precursor cells in 1992, was down-regulated during the development of mouse central nervous system [3]. Afterward, this gene was found in other species and tissues. FAK and SRC were implicated as important targets of NEDD9 and they were phosphorylated and activated mutually, which was regarded as the “core regulation process” of NEDD9 [7]
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