Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

Abstract

Abstract. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC (70-80%). Yes-associated protein 1 (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 kinase 1 (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 86 patients, and in 12 samples of local metastases by quantitative PCR (qPCR). Proteins were semi-quantified in 58 patient 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.

The Immunoexpression of YAP1 and LATS1 Proteins in Clear Cell Renal Cell Carcinoma: Impact on Patients’ Survival

“…In an immunohistochemical study lower LATS1 protein expression was found in renal cancer tissue and it correlated with the clinical stage and pathological grade of ccRCC [ 29 ]. Decreased level of LATS1 immunoreactivity in ccRCC cells, as observed in the present study, corresponds to the analysis of LATS1 gene expression on another set of ccRCC patients where we observed strong association between decreased LATS1 mRNA and protein contents in cancer tissue lysates [ 13 ]. We also identified the possible epigenetic mechanism of decreased LATS1 level: the hypermethylation of LATS1 promoter region was strongly associated with lower LATS1 content [ 13 ].…”

“…These observations are in concordance with our previously performed analysis of the YAP1 expression at the mRNA and protein levels by QPCR and Western blotting techniques, respectively. In that study we showed that YAP1 gene upregulation and worse clinical outcome of ccRCC patients as well as higher YAP1 protein expression in cancer tissue homogenates were associated with the clinical stage and pathomorphological features such as higher TNM and Fuhrman's stages [ 13 ].…”

“…During physiological conditions, YAP1/TEAD complex acts as the transcriptional effector of the Hippo pathway that during development affects organs' size by inhibition of cell proliferation and activation of apoptosis [ 11 ]. The crucial component of the Hippo pathway is serine/threonine-protein kinase 1 (LATS1) that forms Hippo core protein cassette (together with MST2 protein) [ 12 , 13 ]. Hippo pathway negatively regulates YAP1 translocation to nucleus via LATS1-dependent phosphorylation of YAP1 which in turn binds to cytoplasmic 14-3-3 protein.…”

“…In this way the Hippo pathway components control and may inhibit cellular growth. In our previous study we found at both mRNA and protein levels that LATS1 gene expression was downregulated and YAP1 expression upregulated in ccRCC tumor tissues in comparison to corresponding samples of unaltered kidney tissues [ 13 ]. However, the cellular localization and expression of both proteins by immunohistochemistry (IHC) was not performed, and the studies of other authors provided opposite findings [ 15 , 16 ].…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…Histological staining of tumors and experiments in cancer cell lines have implicated YAP/TAZ in several other solid tumor types, including ovarian, [ 120–127 ] prostate, [ 128–134 ] bladder, [ 135–139 ] endometrial, [ 140,141 ] kidney, [ 142–144 ] thyroid, [ 145–149 ] adrenal, [ 150 ] mesothelioma, [ 151,152 ] sarcomas, [ 153–156 ] and epithelioid hemangioendothelioma. [ 157,158 ] In all the above cases, genetically engineered mouse models are still necessary to establish the causative role of Yap/Taz in these tumors in vivo.…”