Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC (70-80%). Yes-associated protein1 (YAP1) protein is a nuclear effector of the Hippo pathway and acts as a transcriptional co-activator of genes involved in the processes of growth and development of tissues. Hippo signaling, with its key kinases, MST2 and large tumor suppressor kinase1 (LATS1), plays a significant role in the negative regulation of the amount and activity of YAP1 protein. Components of the Hippo pathway and YAP1 levels are frequently dysregulated in a variety of tumors, suggestive of their possible involvement in carcinogenesis. Our aim was to evaluate gene and protein expression profiles of YAP1, MST2 and LATS1 and the methylation status of MST2 and LATS1 promoters in ccRCC. mRNA levels of MST2, LATS1 and YAP1 genes were assessed in the tumor and matched normal kidney tissues of 86patients, and in 12samples of local metastases by quantitative PCR (qPCR). Proteins were semi-quantified in 58patient samples by western blotting. Hypermethylation of LATS1 and MST2 promoters was measured by methylation‑specific high‑resolution-melting qPCR. We found that LATS1 promoter hypermethylation, decreased LATS1 mRNA/protein and increased YAP1 mRNA/protein levels in tumor samples were associated with higher TNM and Fuhrman's stages and patient survival. Higher YAP1 mRNA levels were associated with poor outcome (HR=4.03, p=0.036). No changes in MST2 (promoter/mRNA/protein) were found. We propose that deregulation of LATS1 and YAP1 expression is associated with ccRCC progression and poor patient survival. Measurement of YAP1 mRNA levels in paired tumor-normal kidney tissue samples may serve as a new prognostic factor in ccRCC.
Highlights
Clear cell renal cell carcinoma is the most frequent RCC subtype and is characterized by a high mortality rate of 40% within 5 years, due to late diagnosis and distant metastases found in 30 [1] to 80% [2] of RCC patients at the time of examination or within the course of the disease
The Hippo pathway is an important regulator of cell proliferation, apoptosis, stem cell functions [5,6] as well as tissue growth and regeneration
We found a negative correlation between large tumor suppressor kinase 1 (LATS1) protein and Yes-associated protein 1 (YAP1) protein levels when all paired samples of 58 patients were taken into consideration
Summary
Clear cell renal cell carcinoma (ccRCC) is the most frequent RCC subtype and is characterized by a high mortality rate of 40% within 5 years, due to late diagnosis and distant metastases found in 30 [1] to 80% [2] of RCC patients at the time of examination or within the course of the disease. Increased expression of the YAP1 protein is associated with tissue regeneration or carcinogenesis [11,14,15]. The deregulation of the Hippo pathway components and/or YAP1 expression is frequently associated with the progression of various malignancies. Decreased expression of LATS1 gene and protein was observed in breast [16], colorectal [17] and non-small cell lung cancers [18], whereas lower MST2 mRNA and protein levels were reported in hepatocellular carcinoma [19] and malignant mesothelioma [20]. Since to date no quantitative analyses of the expression of the Hippo pathway effector, YAP1, and its key components, MST2 and LATS1 kinases, have been assessed in ccRCC, we decided to compare their mRNA and protein levels in tumor and normal kidney tissues, and in metastases of ccRCC.
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