A Novel Biomarker SNHG11 Promotes Tumor Progression and Oxidative Phosphorylation in Clear Cell Renal Cell Carcinoma

Abstract

Kidney renal clear cell carcinoma (KIRC) is the most common and aggressive subtype of renal cell carcinoma and is characterized by poor prognosis and high molecular heterogeneity. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer, yet the functional role of SNHG11 in KIRC remains unclear. In this study, we perform integrated multiomics analysis using data from the TCGA and ICGC cohorts and reveal that SNHG11, a methylation-associated lncRNA, is significantly correlated with poor clinical outcomes. In vitro and in vivo assays demonstrate that SNHG11 promotes tumor proliferation and progression. Mechanistically, SNHG11 enhances oxidative phosphorylation, as evidenced by increased ATP production, disrupted mitochondrial membrane potential, and altered NAD+/NADH ratios. Furthermore, SNHG11 expression is associated with somatic mutation patterns, particularly those involving BAP1 and PBRM1, indicating potential crosstalk between epigenetic regulation and genetic alterations. These findings reveal that SNHG11 is a novel biomarker in KIRC and a potential therapeutic target.

1. Introduction

Renal cell carcinoma (RCC) ranks among the most prevalent malignant neoplasms worldwide and is characterized by significant morbidity and mortality [1]. Recent epidemiological data indicate that kidney cancer is among the six leading cancers with persistently increasing incidence rates [1]. The primary histological subtypes of RCC include kidney renal clear cell carcinoma (KIRC), chromophobe renal cell carcinoma, and papillary renal cell carcinoma, with KIRC constituting approximately 80% of all RCC cases [2]. KIRC, the predominant subtype, exhibits marked biological aggressiveness, with a propensity for postoperative metastasis and limited responsiveness to conventional therapies such as radiotherapy and chemotherapy [3]. This often leads to the development of therapeutic resistance and, consequently, poor clinical outcomes [2]. Given the pronounced heterogeneity of KIRC, there is an urgent need to identify novel prognostic biomarkers to stratify patients effectively and to discover targeted therapeutic agents to address the demands of personalized medicine.

Over 98% of the human genome is transcribed into RNA molecules with minimal or no protein-coding capacity, among which long noncoding RNAs (lncRNAs) play pivotal roles as epigenetic modulators of gene expression [4]. lncRNAs constitute a diverse group of RNA molecules exceeding 200 nucleotides in length. Despite the identification of more than 170,000 lncRNAs in the human genome, the functional roles and annotations of them remain largely unexplored [5,6]. Increasing evidence highlights the pivotal role of lncRNAs in cancer progression [7]. For example, recent studies have demonstrated that the lncRNA WDR11-DT enhances radiosensitivity in non-small cell lung cancer by promoting PARP1 degradation and inducing homologous recombination deficiency [8]. Similarly, the lncRNA LRTOR has been shown to drive osimertinib resistance in non-small cell lung cancer by amplifying the YAP-positive feedback loop [5]. The lncRNA LIMD1-AS1 enhances TGF-β/SMAD signaling through a positive feedback loop by promoting the formation of the SMAD3/p300 transcriptional complex, thereby increasing the migration and invasion abilities of breast cancer cells [9]. In the context of KIRC, lncRNAs also play significant roles. Notably, an ultraconserved snoRNA-like element within the lncRNA CRNDE has been found to promote ribosome biogenesis and cellular proliferation [6,10]. Recent advances have significantly expanded our understanding of lncRNAs in the context of KIRC [11,12]. Several lncRNAs have emerged as promising candidates for diagnostic and prognostic biomarkers in KIRC. For example, lncARSR has been identified as a potential indicator of sunitinib resistance and a candidate therapeutic target [13]. Similarly, LINC00926 shows promise as a novel biomarker for predicting responses to immune checkpoint blockade (ICB) immunotherapy in RCC while also serving as a potential therapeutic target [14]. Mechanistically, lncRNAs exert regulatory effects by interacting with various cellular components, including proteins, DNA, RNA, and chromatin remodeling complexes, thereby modulating the expression of target genes [11]. Additionally, a subset of lncRNAs has been found to encode functional peptides, further expanding their biological roles [12].