Abstract
The third member of transforming acidic coiled-coil protein (TACC) family, TACC3, has been shown to be an important player in the regulation of centrosome/microtubule dynamics during mitosis and found to be deregulated in a variety of human malignancies. Our previous studies have suggested that TACC3 may be involved in cervical cancer progression and chemoresistance, and its overexpression can induce epithelial-mesenchymal transition (EMT) by activating the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signal transduction pathways. However, the upstream mechanisms of TACC3-mediated EMT and its functional/clinical importance in human cervical cancer remain elusive. Epidermal growth factor (EGF) has been shown to be a potent inducer of EMT in cervical cancer and associated with tumor invasion and metastasis. In this study, we found that TACC3 is overexpressed in cervical cancer and can be induced upon EGF stimulation. The induction of TACC3 by EGF is dependent on the tyrosine kinase activity of the EGF receptor (EGFR). Intriguingly, depletion of TACC3 abolishes EGF-mediated EMT, suggesting that TACC3 is required for EGF/EGFR-driven EMT process. Moreover, Snail, a key player in EGF-mediated EMT, is found to be correlated with the expression of TACC3 in cervical cancer. Collectively, our study highlights a novel function for TACC3 in EGF-mediated EMT process and suggests that targeting of TACC3 may be an attractive strategy to treat cervical cancers driven by EGF/EGFR signaling pathways.
Highlights
Epithelial-mensenchymal transition (EMT) is a highly conserved biological process that results in a conversion of polarized epithelial cells to mesenchymal cell types characterized by the loss of E-cadherin-mediated cell-cell contacts as well as the acquisition of increased migratory and invasive potentials [1,2,3,4,5,6,7,8,9]
TACC3 is Overexpressed in Cervical Cancer To investigate the clinical importance of TACC3 in human cervical cancer, we first examined the expression of TACC3 mRNA in cervical cancer using the publicly available Oncomine database [65] and determined that TACC3 is highly expressed in cervical cancer [66,67]
There was no significant difference in the expression of TACC3 between Human papillomaviruses (HPVs)-negative C33A and other cells carrying HPV oncogenes (Ect1/E6E7, CaSki, HeLa and SiHa), suggesting that HPV infection may not be responsible for the overexpression of TACC3
Summary
Epithelial-mensenchymal transition (EMT) is a highly conserved biological process that results in a conversion of polarized epithelial cells to mesenchymal cell types characterized by the loss of E-cadherin-mediated cell-cell contacts as well as the acquisition of increased migratory and invasive potentials [1,2,3,4,5,6,7,8,9]. Transcriptional factors Snail, Slug, Twist and Zeb have been identified as negative regulators of E-cadherin and are considered to be potent oncogenic inducers of EMT [10,11,12,13,14]. Epidermal growth factor (EGF) has been shown to be one of the most potent inducers of EMT in cervical cancer and associated with cervical stromal invasion and nodal metastasis [15,19]. Chronic EGF treatment induces EMT via up-regulation of EMT-inducing transcription factor Snail in cervical cancer cells, and EGF-mediated EMT is correlated with EGF receptor (EGFR) overexpression and clinical progression of cervical cancer [15,20]. The expression of EGFR has been found to be overexpressed in cervical cancer [21]
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