The present study elucidates the clinical significance, intrinsic mechanisms, and biological functions of piRNAs and circRNAs in RCC, providing invaluable insights for cancer exploration and the development of novel therapeutic targets in a wide array of cancers including testicular tumors5, cervical cancer6, epithelial ovarian cancer7, gastric cancer8, breast cancer9, multiple myeloma10,liver cancer11,colorectal cancer12,and bladder cancer13.
Notably, piRNAs have been implicated in the de novo regulation of DNA methylation 14–16, and the Piwi-piRNA pathway has been demonstrated to uphold genome integrity in germline stem cells by repressing transposition factors through DNA methylation 17–19. Furthermore, Zhao et al. investigated the expression levels of mitochondrial piR-51810 and piR-34536 in tissues and serum samples from ccRCC patients, revealing significantly decreased expression levels in ccRCC tissues compared to normal tissues20. Emerging evidence suggests that this silencing mechanism also extends to non-germline genomic regions with tumor backgrounds, such as tumor suppressor genes, resulting in an aberrant "stem-like" state and subsequent tumorigenesis21–22. The downregulation of mitochondrial piRNAs was found to be negatively associated with the prognosis of ccRCC patients, highlighting the clinical relevance of these non-coding RNAs. However, the precise functions of piRNAs and their generation pathway genes remain elusive in ccRCC. It is suggested that piRNAs act as epigenetic regulators involved in tumor angiogenesis, invasiveness, growth, and metastasis23–24.
The role of circRNAs in kidney disease is currently a subject of intense research, captivating the attention of scholars worldwide. Emerging evidence suggests that circRNAs possess immense potential to serve as invaluable biomarkers for disease activity and hold promise as therapeutic targets. Numerous ongoing studies are fervently focused on unraveling the intricate correlation between circRNAs and various types of human cancers25–26. Remarkably, circRNAs play a pivotal role in orchestrating cellular metabolism, with specific circRNAs implicated in modulating crucial processes such as glycolysis, lipolysis, lipogenesis, and oxidative phosphorylation. This profound understanding further enhances our comprehension of aberrant cell metabolism in cancer27.Furthermore, extracellular vesicle-derived circRNAs possess the capacity to be internalized by distal cells and exert a significant impact on crucial biological pathways within these recipient cells, thereby potentially facilitating tumor metastasis. Therefore, circRNAs demonstrate promising potential as diagnostic and prognostic biomarkers, as well as therapeutic targets for renal cancer 28. In studies focused on kidney cancer, hsa_circ_0035483 has been shown to contribute to gemcitabine-induced autophagy, consequently enhancing resistance of RCC towards gemcitabine treatment. By functioning as a competitive endogenous RNA for hsa-miR-335, hsa_circ_0035483 augments resistance against gemcitabine and promotes tumor growth through modulation of cyclin B1 (CCNB1) expression 29. Conversely, silencing of hsa_circ_0035483 enhances in vivo sensitivity to gemcitabine. Moreover, circRNAs display distinct expression patterns in response to cisplatin treatment, implying their involvement in the pathophysiology of cisplatin-induced nephrotoxicity. Investigation into the potential impact of radiation therapy on circRNA expression profiles revealed significant alterations upon irradiation of human embryonic kidney (HEK293T) cells. These findings suggest that CircRNAs may function as regulators of drug resistance in human cancer therapy and could be implicated in addressing drug resistance issues specific to kidney cancer treatment 30. Therefore, elucidating the role and mechanism by which circRNAs function in kidney cancer is an urgent topic necessitating further investigation. Moreover, enclosed within extracellular vesicles, circRNAs can be internalized by distant cells, exerting influence on crucial biological pathways in these recipient cells and potentially facilitating tumor metastasis. Hence, circRNAs exhibit immense potential as diagnostic and prognostic biomarkers as well as appealing therapeutic targets for renal cancer.
Our study aims to investigate the roles and mechanisms of circRNAs and piRNAs in ccRCC. This involves utilizing high-throughput sequencing to detect aberrantly expressed circRNAs and piRNAs in ccRCC, followed by screening for differentially expressed ones and validating them using clinical samples. Furthermore, we analyze the diagnostic value of circRNAs and piRNAs in ccRCC. Key findings include the identification of 17 upregulated and 5 downregulated piRNAs in tumor tissues compared to normal tissues, as well as 694 downregulated and 490 upregulated circRNAs in ccRCC tissues. Specifically, significant reductions were observed in specific piRNA species such as piR-has-150997, 133872, 132556, 154502, and uniq-84737 when comparing ccRCC samples with normal tissues. Additionally, elevated expression levels were detected for circABCC1 and circNETO2_006 while decreased expression was found for circARID1B_037 in ccRCC tissues. We evaluated the diagnostic performance of these identified circRNAs and piRNAs using AUC values which indicated good diagnostic potential. Moreover, a combined diagnostic model based on differentially expressed circRNAs and piRNAs demonstrated even higher AUC values suggesting its potential use as a superior diagnostic marker system for ccRCC.
The main objective of this study was focused on detection and verification of pathological specimens, however, it should be noted that the evidence provided here is restricted to only one source with a limited number of samples. In order to augment the significance attributed to piRNAs and circRNAs in both diagnosis as well as treatment approaches for renal cell carcinoma (ccRCC), expanding sample sizes for further validation is highly recommended. Additionally, there exists a research gap pertaining to variations in expression levels among these biomarkers within urine, exosomes, as well as serum when considering ccRCC diagnosis or treatment options. Future research endeavors should strive towards addressing this knowledge void through refinement of research plans along with exploration into new investigative pathways, thus contributing towards an enhanced comprehension surrounding potential diagnostic capabilities alongside therapeutic roles played by piRNAs and circRNA molecules within ccRCC management practices. The ultimate goal of these endeavors is to develop pioneering strategies that efficiently handle patients with ccRCC.