Transforming acidic coiled-coil-containing protein 3 (TACC3) overexpression in hepatocellular carcinomas is associated with "stemness" and epithelial-mesenchymal transition-related marker expression and a poor prognosis

Abstract

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.

Keywords: Epithelial-mesenchymal transition; Hepatocellular carcinoma; Immunohistochemistry; Prognosis; Stemness; TACC3.