Renal Cell Tumors: Uncovering the Biomarker Potential of ncRNAs

Abstract

Renal cell tumors (RCT) remain as one of the most common and lethal urological tumors worldwide. Discrimination between (1) benign and malignant disease, (2) indolent and aggressive tumors, and (3) patient responsiveness to a specific therapy is of major clinical importance, allowing for a more efficient patient management. Nonetheless, currently available tools provide limited information and novel strategies are needed. Over the years, a putative role of non-coding RNAs (ncRNAs) as disease biomarkers has gained relevance and is now one of the most prolific fields in biological sciences. Herein, we extensively sought the most significant reports on ncRNAs as potential RCTs' diagnostic, prognostic, predictive, and monitoring biomarkers. We could conclude that ncRNAs, either alone or in combination with currently used clinical and pathological parameters, might represent key elements to improve patient management, potentiating the implementation of precision medicine. Nevertheless, most ncRNA biomarkers require large-scale validation studies, prior to clinical implementation.

Keywords: Renal cell tumors; biomarkers; diagnosis; liquid biopsies; lncRNA; miRNA; non-coding RNAs; prognosis; renal cell carcinoma.

Figure 1

Schematic representation of epigenetic machinery components. DNA methylation is catalyzed by DNA methyl transferases (DNMT) and consists of covalent addition of a methyl group to the 5-carbon of the cytosine ring resulting in 5-methylcytosine (5-mC). Histone post-transcriptional modifications constitute another type of epigenetic-based gene regulatory mechanism. These reactions (e.g., acetylation and methylation) occur in the residues of histone tails and are extremely refined, being catalyzed by highly regulated enzymes. In addition, histones might also have variants, which alter nucleosome functionality. Chromatin remodeling complexes, such as SWItch/Sucrose Non-Fermentable (SWI/SNF), Imitation SWI (ISWI), INO80, and Nucleosome Remodeling Deacetylase (NuRD), alter chromatin architecture, through direct interaction with nucleosomes. Finally, non-coding RNAs, namely small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) post-transcriptionally regulate gene expression, both in the nucleus and cytoplasm. Created by BioRender.com (https://biorender.com/)

Figure 2

Summary of the most promising biomarker candidates for RCT. (A) Several ncRNAs have been proposed as ancillary tools for distinguishing tumor growth from normal tissue. Arrows represent each ncRNA expression level in RCT, comparing to normal samples (“red”—upregulated; “green”—downregulated). (B) Besides the potential use of ncRNAs to detect tumorigenesis, some were reported as capable to differentiate both malignant from benign lesions, and benign from asymptomatic conditions. The arrows represent ncRNA expression level (upper) in RCC, comparing to RCT and (lower) renal benign tumors, comparing to normal samples (“red”—upregulated; “green”—downregulated). (C) The potential of ncRNAs to stratify high-risk patients has been highly studied in recent years. The arrows represent each ncRNA expression level in patients displaying worse survival, comparing to those with better survival (“red”—upregulated; “green”—downregulated). (D) Lastly, ncRNA expression level has been proposed as potential predictor of therapy response. The arrows show the biological status of each ncRNA for a better response to therapy (“red’—upregulated; “green”—downregulated).