Abstract
Background/Aims: Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) activation has been implicated in hepatocarcinogenesis and hepatic progenitor cell differentiation, and hypoxia has been shown to induce nuclear translocation of YAP in cancer cells. Here, we aimed to investigate the relationship between hypoxia, YAP and TAZ expression and stemness-related marker expression in human hepatocellular carcinomas (HCCs) and its clinical implications. Methods: Immunohistochemical stains were performed on tissue microarrays from 305 surgically resected HCCs, and the expression status of YAP and TAZ were correlated with CAIX, stemness markers (K19, EpCAM) and epithelial-mesenchymal transition (EMT)-related markers (uPAR, ezrin). The clinicopathological significance of YAP/TAZ expression was analyzed with relation to CAIX expression status. Results: YAP and TAZ expression were seen in 13.4 and 4.3% of HCCs, respectively. YAP/TAZ-positive HCCs frequently demonstrated higher serum AFP levels, microvascular invasion, advanced tumor stage, increased proliferative activity and expression of stemness- and EMT-related markers, CAIX, p53 and Smad2/3 (p < 0.05, all). Interestingly, YAP/TAZ-positivity was associated with microvascular invasion, higher serum AFP levels, stemness and EMT-related marker expression only in tumors expressing CAIX (p < 0.05, all), while these associations were not seen in CAIX-negative HCCs. Conclusions: YAP/TAZ expression is associated with vascular invasion, stemness and EMT in HCCs with hypoxia marker expression. The effect of Hippo signaling pathway deregulation in HCC may depend on the presence or absence of a hypoxic microenvironment, and hypoxia marker expression status should be taken into account when considering the use of YAP/TAZ as markers of aggressive biologic behavior in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the fourth leading cause of cancerrelated deaths
There was a positive correlation between Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) expression status (p < 0.001)
We demonstrate that the expression of YAP/TAZ in HCCs is associated with “stemness,” epithelial-mesenchymal transition (EMT) and aggressive clinicopathological features as previously reported, this relationship is seen only in HCCs with hypoxia marker expression
Summary
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the fourth leading cause of cancerrelated deaths. A subset of HCCs (5–20%) have been demonstrated to express markers associated with “stemness,” including keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), CD133, CD117/c-kit and SALL4, and these HCCs have been associated with aggressive biological behavior and poor survival [1]. Activated YAP has been associated with aggressive behavior of various malignant neoplasms, including cell proliferation, stemness, epithelial-mesenchymal transition (EMT) and chemoresistance [10,11,12,13,14]. YAP protein expression has been demonstrated in stemness-marker expressing HCCs and in combined hepatocellular-cholangiocarcinomas, both of which have been postulated to show features of hepatic progenitor cell differentiation [11, 15]
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