10460

TACC3

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.

There is accumulating evidence that hepatocellular carcinomas (HCCs) expressing "stemness"-related markers, e.g., keratin 19 (K19) and epithelial cell adhesion molecule (EpCAM), are associated with aggressive biological behavior. In order to further investigate the molecular characteristics of this subgroup of HCCs, we examined copy number alterations of K19-positive and K19-negative HCCs and found frequent amplifications of the 4p16.3 locus containing the TACC3 gene, which has previously not been described in HCCs. We performed an immunohistochemical analysis of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in HCCs in whole tissue sections and tissue microarrays and examined the clinicopathological characteristics of TACC3-overexpressing HCCs in relation to stemness-related marker (K19, EpCAM) expression, epithelial-mesenchymal transition (EMT)-related proteins, and survival. Cytoplasmic TACC3 protein expression was seen in 7/7 whole tissue sections of K19-positive HCCs, while TACC3 expression was negative or patchy in K19-negative cases. In the tissue microarray cohort, TACC3 was overexpressed in 105/188 (55.9 %) HCCs and was associated with poor differentiation (p = 0.028), major vascular invasion (p = 0.039), higher tumor stages (p = 0.015), younger age (p = 0.003), higher proliferative activity (p < 0.001), and more frequent multipolar mitoses (p < 0.001). TACC3 expression was significantly correlated with K19 (p = 0.010) and EpCAM (p < 0.001) positivity. In addition, TACC3 overexpression was associated with frequent expression of S100A4, uPAR, and ezrin (p < 0.001, all) and loss of E-cadherin expression (p = 0.014), and overall survival was significantly decreased in patients with TACC3-positive HCCs (p = 0.014). In conclusion, TACC3 overexpression was associated with clinicopathological features of aggressiveness, increased EMT-related protein expression, and poor survival, suggesting a potential role for TACC3 as a prognostic biomarker and therapeutic target in HCC.