Abstract
Pediatric hepatocellular carcinoma (HCC) is a rare tumor which is associated with an extremely high mortality rate due to lack of effective chemotherapy. Recently, the Hippo pathway and its transcriptional co-activator Yes-associated protein (YAP) have been shown to play a role in hepatocyte proliferation and development of HCC in animal models. Therefore, we sought to examine the activity of YAP and the expression of Hippo pathway components in tumor and non-neoplastic liver tissue from 7 pediatric patients with moderately differentiated HCC. None of the patients had underlying cirrhosis or viral hepatitis, which is commonly seen in adults with HCC. This highlights a major difference in the pathogenesis of HCC between children and adults. We found a statistically significant increase in YAP nuclear localization in 100% of tumors. YAP target gene (CCNE1, CTGF, Cyr61) mRNA expression was also increased in the tumors that had the most significant increase in YAP nuclear localization. Based on Ki67 co-localization studies YAP nuclear localization was not simply a marker of proliferation. Our results demonstrate a clear increase in YAP activity in moderately differentiated pediatric HCC, providing evidence that it may play an important role in tumor survival and propagation.
Highlights
Histologic vascular invasion phosphorylation, cytoplasmic retention, and degradation[9]
Our results demonstrate that Yes-associated protein (YAP) nuclear localization is significantly increased in moderately differentiated pediatric hepatocellular carcinoma (HCC), it is not a marker of proliferation in tumor cells since on average only 50% of Ki67 positive cells were YAP positive
Given the association between YAP and hepatocarcinogenesis in murine models together with the findings that YAP plays a role in hepatocyte proliferation[9,18], our results suggest that the observed increase in YAP nuclear localization in pediatric HCC may be important to its biology
Summary
Histologic vascular invasion phosphorylation, cytoplasmic retention, and degradation[9]. Outside of areas where viral hepatitis is endemic, 60–70% of HCC in the pediatric population arises in a background of non-cirrhotic liver[21,22]. This contrast highlights a potentially significant difference in the pathogenesis of HCC in these two populations[6]. It raises the question of whether these distinctions are reflected in the inhibition of the Hippo pathway and YAP nuclear localization. We examined the expression of known Hippo pathway core kinases, as well as related upstream and downstream genes
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