Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, 3000 Leuven, Belgium.
Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Americas, Quito 170503, Ecuador.
Int J Mol Sci. 2019 Feb 1;20(3):638. doi: 10.3390/ijms20030638.
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19⁺), hepatocellular carcinoma keratin 19 negative (HCC K19), combined hepatocellular⁻cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19 HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19 HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.
原发性肝癌包括一组不同的肝脏肿瘤。这些肿瘤的异质性被认为是寻找有效治疗方法的障碍之一。Hippo 通路及其下游转录共激活因子 Yes 相关蛋白（YAP）和 PDZ 结合基序转录共激活因子（TAZ）在原发性肝癌的发生中起着决定性作用。因此，我们检查了 YAP 和 TAZ 在 141 例肝细胞癌角蛋白 19 阳性（HCC K19⁺）、肝细胞癌角蛋白 19 阴性（HCC K19）、肝细胞癌-胆管细胞癌（cHCC-CCA）或胆管癌（CCA）患者中的表达模式。所有 cHCC-CCA 和 CCA 患者的 YAP 和 TAZ 表达水平均较高，而 HCC 组只有部分患者为阳性。值得注意的是，我们发现这两个标志物的组织评分在 cHCC-CCA 的挑战性诊断中很有用。此外，在 cHCC-CCA 的肝细胞和胆管细胞成分中观察到 YAP 和 TAZ 的阳性表达，这表明 cHCC-CCA 具有单细胞起源。在 K19 HCC 组中，我们的结果表明，YAP 的表达在细胞质中观察到是预后不良的统计学显著预测因子。TAZ 的核表达是 K19 HCC 患者无病生存期和总生存期更特异和独立的预后预测因子。因此，我们的结果确定了不同水平的 YAP/TAZ 表达在各种肝癌中可用于诊断。
