A specific splicing isoform of RNASET2 is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). However, the interplay between wild type RNASET2 and its splice variant and how this might contribute to the pathogenesis of ccRCC remains poorly understood. We sought to better understand the relationship of RNASET2 in the pathogenesis of ccRCC and the interplay with a pathogenic splicing isoform (RNASET2-SV) and the tumor immune microenvironment. Using data from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), we correlated clinical variables to RNASET2 expression and the presence of a specific RNASET2-SV. Immunohistochemical staining with matched RNA sequencing of ccRCC patients was then utilized to understand the spatial relationships of RNASET2 with immune cells. Finally, in vitro studies were performed to demonstrate the oncogenic role of RNASET2 and highlight its potential mechanisms. RNASET2 gene expression is associated with higher grader tumors and worse overall survival in the TCGA cohort. The presence of the RNASET2-SV was associated with increased expression of the wild-type RNASET2 protein and epigenetic modifications of the gene. Immunohistochemical staining revealed increased intracellular accumulation of RNASET2 in patients with increased RNA expression of RNASET2-SV. In vitro experiments reveal that this accumulation results in increased cell proliferation, potentially from altered metabolic pathways. RNASET2 exhibits a tumor-promoting role in the pathogenesis of ccRCC that is increased in the presence of a specific RNASET2-SV and associated with changes in the cellular localization of the protein.
Laboratory investigation; a journal of technical methods and pathology. 2024 Feb 29 [Epub ahead of print]
Taylor Peak, Yijun Tian, Aman Patel, Tim Shaw, Alyssa Obermayer, Jose Laborde, Youngchul Kim, Joseph Johnson, Paul Stewart, Bin Fang, Jamie K Teer, John Koomen, Anders Berglund, Doug Marchion, Natasha Francis, Paola Ramos Echevarria, Jasreman Dhillon, Noel Clark, Andrew Chang, Wade Sexton, Logan Zemp, Jad Chahoud, Liang Wang, Brandon Manley
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fl, USA. Electronic address: ., Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fl, USA., Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fl, USA., Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fl, USA., Analytic Microcopy Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Tissue Core Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fl, USA. Electronic address: .