Correlation without causality between BAP1 loss and the metastasis-associated <i>miR-183/96/182</i> cluster expression in renal cell carcinoma.

Abstract

531 Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and is characterized by high genetic heterogeneity. Mutations in BRCA-associated protein 1 (BAP1) are associated with more aggressive tumor biology and poorer survival outcomes. MicroRNAs (miRNAs) play a central role in gene regulation and have been investigated as potential biomarkers in various cancer types. Approximately one-third of ccRCC patients present with metastatic disease at diagnosis, while another third develop metastases during disease progression. Due to the lack of valid predictive biomarkers, we analyzed the expression profiles of various miRNA clusters in ccRCC. Methods: miRNA expression profiles were analyzed from 120 ccRCC tumor samples obtained from the University of Texas Southwestern Medical Center as well as from the KIRC-TCGA database. miRNA expression levels were validated using quantitative RT-PCR (qRT-PCR) and correlated with clinicopathological parameters. Additionally, functional analyses were conducted in cell culture and mouse models to investigate the BAP1-mediated regulation of the miR-183/96/182 cluster. Results: A significant upregulation of the miR-183/96/182 cluster was observed in BAP1 -mutated ccRCC tumors compared to PBRM1 -mutated or wild-type tumors. Increased miRNA expression correlated with significantly poorer overall survival and shorter metastasis-free survival. Furthermore, high expression was associated with more aggressive histopathological characteristics, including advanced tumor stage and rhabdoid differentiation. In mouse models, overexpression of miR-182 significantly promoted metastasis. Luciferase reporter assays suggested that BAP1 may influence miRNA cluster expression at the promoter level. However, no direct regulatory mechanism involving BAP1 was identified. Conclusions: Our findings demonstrate that increased expression of the miR-183/96/182 cluster is a poor prognostic marker in ccRCC, associated with reduced overall survival and shorter metastasis-free survival, similarly to the effects of BAP1 loss. Despite the observed correlation, a causal relationship between BAP1 loss and miR-183/96/182 dysregulation could not be established at the molecular level. Nevertheless, the expression of this miRNA cluster may serve as a potential biomarker for risk stratification and therapeutic decision-making in ccRCC patients.