Background: overexpression of the oncogene Yes-associated protein 1 (YAP1), a Hippo pathway target, associates with increased cell proliferation in some human cancers. There is not data on adrenocortical tumors (ACT). YAP1 is a potential target of Wnt/β-catenin pathway, which plays an important role in ACTs.
Objective and hypotheses: to evaluate the role of YAP1 and its interaction with the Wnt/β-catenin pathway in ACT.
Method: Association between YAP1 mRNA and protein expression and clinical, biochemical, pathological and patients outcome data was evaluated in 42 pediatric patients with ACT (81% females; median age: 31 months (5185)). The expression data was compared to 21 normal pediatric adrenal cortices and 32 normal fetal adrenal cortices. In addition, in vitro experiments blocking the TCF/β-catenin complex with PNU-74654 in H295 adrenal tumor cells analyzed the interaction between YAP1 and the Wnt/β-catenin pathway, which is activated in H295 cells due to presence of the p.Ser45Pro β-catenin mutation. YAP1 expression was evaluated by qPCR, Immunohistochemistry (IHC) and western blot.
Results: IHC showed high nuclear expression of YAP1 in fetal adrenals but not in postnatal normal adrenals. YAP1 nuclear accumulation was observed in 97% of the tumor samples. Overall, no differential YAP1 mRNA expression was found between control adrenals and ACTs. However, higher YAP1 mRNA expression in ACTs was significantly associated with death (P=0.02) and recurrence/metastasis (P=0.002). KaplanMeier curve and log-rank test showed that higher YAP1 expression was associated with lower survival (P=0.02). Bayesian linear regression also showed higher YAP1 mRNA expression in patients with recurrence/metastasis (5.02; 95% CI: 2.097.94), death (5.09; 95% CI: 2.098.16) and advanced tumor stage (4.63; 95% CI: 0.618.64). In vitro data showed that in adrenal cells, YAP1 is also a Wnt/β-catenin target gene. The inhibition of the Wnt/β-catenin signaling diminished YAP1 protein expression by 44, 58, and 81% after 48 h with 50, 100, and 200 μM PNU-74654 respectively.
Conclusion: Higher expression of the oncogene YAP1 appears to be a marker of poor prognosis and lower survival rates in pediatric patients with ACT. These original data highlight YAP1 as a potential target to treat patients with invasive or recurrent adrenal tumors.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology