This study systematically investigates the roles of messenger RNAs (mRNAs) and microRNAs (miRNAs) in Renal Cell Carcinoma (RCC) and their potential as diagnostic and prognostic biomarkers via a stratification approach. By utilizing The Cancer Genome Atlas (TCGA) database, differentially expressed mRNAs (namely DEGs) and miRNAs (namely DEMs) are identified, and survival prognosis-related biomarkers are determined through Kaplan-Meier analysis and lasso regression. Prognostic models are established for RCC ethnicity, pathologic stages, and metastatic status, with validation through plotting risk heatmaps, risk curves, survival curves, and Receiver Operating Characteristic (ROC) curves. A total of 45 mRNA and 33 miRNA biomarkers are identified across different prognostic models, resulting in enhanced prediction accuracy with increased stratification. The literature review confirms abnormal expressions of 28 prognostic RNAs reported in experiments and 15 prognostic RNAs reported in bioinformatics studies. The study also introduces 35 novel prognostic RNAs as potential treatment targets for RCC. The mRNA+miRNA prognostic models exhibit the most robust predictive capability, indicating their potential clinical relevance. Overall, the study contributes to a precise prognosis of RCC by exploring novel biomarkers and potential therapeutic targets.
R. J. Motzer, E. Jonasch, N. Agarwal, A. Alva, M. Baine, K. Beckermann, M. I. Carlo, T. K. Choueiri, B. A. Costello, and I. H. Derweesh, et al., Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology, J. Natl. Compr. Canc. Netw., vol. 20, no. 1, pp. 71–90, 2022.
R. L. Siegel, K. D. Miller, N. S. Wagle, and A. Jemal, Cancer statistics, 2023, CA. Cancer J. Clin., vol. 73, no. 1, pp. 17–48, 2023.
W. H. Chow, L. M. Dong, and S. S. Devesa, Epidemiology and risk factors for kidney cancer, Nat. Rev. Urol., vol. 7, no. 5, pp. 245–257, 2010.
V. Ficarra, R. Righetti, S. Pilloni, A. D’amico, N. Maffei, G. Novella, L. Zanolla, G. Malossini, and G. Mobilio, Prognostic factors in patients with renal cell carcinoma: Retrospective analysis of 675 cases, Eur. Urol., vol. 41, no. 2, pp. 190–198, 2002.
J. J. Hsieh, M. P. Purdue, S. Signoretti, C. Swanton, L. Albiges, M. Schmidinger, D. Y. Heng, J. Larkin, and V. Ficarra, Renal cell carcinoma, Nat. Rev. Dis. Primers., vol. 3, p. 17009, 2017.
P. Zareba and P. Russo, The prognostic significance of nodal disease burden in patients with lymph node metastases from renal cell carcinoma, Urol. Oncol., vol. 37, no. 5, pp. 302.e1–302.e6, 2019.
N. Robichaud, N. Sonenberg, D. Ruggero, and R. J. Schneider, Translational control in cancer, Cold Spring Harb Perspect Biol., vol. 11, no. 7, p. a032896, 2019.
X. Ren, X. Chen, Y. Ji, L. Li, Y. Li, C. Qin, and K. Fang, Upregulation of KIF20A promotes tumor proliferation and invasion in renal clear cell carcinoma and is associated with adverse clinical outcome, Aging (Albany NY), vol. 12, no. 24, pp. 25878–25894, 2020.
S. Mishra, T. Yadav, and V. Rani, Exploring miRNA based approaches in cancer diagnostics and therapeutics, Crit. Rev. Oncol. Hematol., vol. 98, pp. 12–23, 2016.
H. He, L. Wang, W. Zhou, Z. Zhang, L. Wang, S. Xu, D. Wang, J. Dong, C. Tang, H. Tang, X. Yi, and J. Ge, MicroRNA expression profiling in clear cell renal cell carcinoma: Identification and functional validation of key mirNAs, PLoS One, vol. 10, no. 5, p. e0125672, 2015.
E. Y. Dessie, J. J. P. Tsai, J. G. Chang, and K. L. Ng, A novel miRNA-based classification model of risks and stages for clear cell renal cell carcinoma patients, BMC Bioinform., vol. 22, no. 10, p. 270, 2021.
A. Sánchez-Gastaldo, E. Kempf, A. González Del Alba, and I. Duran, Systemic treatment of renal cell cancer: A comprehensive review, Cancer Treat. Rev., vol. 60, pp. 77–89, 2017.
A. Znaor, J. Lortet-Tieulent, M. Laversanne, A. Jemal, and F. Bray, International variations and trends in renal cell carcinoma incidence and mortality, Eur. Urol., vol. 67, no. 3, pp. 519–530, 2015.
J. S. Yuan, Z. S. Chen, K. Wang, and Z. L. Zhang, Holliday junction-recognition protein modulates apoptosis, cell cycle arrest and reactive oxygen species stress in human renal cell carcinoma, Oncol. Rep., vol. 44, no. 3, pp. 1246–1254, 2020.
W. Wei, Y. Lv, Z. Gan, Y. Zhang, X. Han, and Z. Xu, Identification of key genes involved in the metastasis of clear cell renal cell carcinoma, Oncol. Lett., vol. 17, no. 5, pp. 4321–4328, 2019.
S. Liu, Y. Wang, C. Miao, Q. Xing, and Z. Wang, High expression of CDCA7 predicts poor prognosis for clear cell renal cell carcinoma and explores its associations with immunity, Cancer Cell Int., vol. 21, no. 1, p. 140, 2021.
W. Han, B. Fan, Y. Huang, X. Wang, Z. Zhang, G. Gu, and Z. Liu, Construction and validation of a prognostic model of RNA binding proteins in clear cell renal carcinoma, BMC Nephrol., vol. 23, no. 1, p. 172, 2022.
Y. Qian, Y. Li, K. Chen, N. Liu, X. Hong, D. Wu, Z. Xu, L. Zhou, L. Xu, and R. Jia, et al., Pan-cancer transcriptomic analysis identifies PLK1 crucial for the tumorigenesis of clear cell renal cell carcinoma, J. Inflamm. Res., vol. 15, pp. 1099–1116, 2022.
G. Sun, Y. Ge, Y. Zhang, L. Yan, X. Wu, W. Ouyang, Z. Wang, B. Ding, Y. Zhang, and G. Long, et al., Transcription factors BARX1 and DLX4 contribute to progression of clear cell renal cell carcinoma via promoting proliferation and epithelial-mesenchymal transition, Front. Mol. Biosci., vol. 8, p. 626328, 2021.
Y. Wang, S. Liu, Y. Chen, B. Zhu, and Q. Xing, Survival prognosis, tumor immune landscape, and immune responses of PPP1R18 in kidney renal clear cell carcinoma and its potentially double mechanisms, World J. Oncol., vol. 13, no. 1, pp. 27–37, 2022.
H. Fang, Z. Peng, B. Tan, N. Peng, B. Li, D. He, M. Xu, and Z. Yang, The involvement of PDIA2 gene in the progression of renal cell carcinoma is potentially through regulation of JNK signaling pathway, Clin. Transl. Oncol., vol. 25, no. 10, pp. 2938–2949, 2023.
Y. Liu, H. Wang, B. Ni, J. Zhang, S. Li, Y. Huang, Y. Cai, H. Mei, and Z. Li, Loss of KCNJ15 expression promotes malignant phenotypes and correlates with poor prognosis in renal carcinoma, Cancer Manag. Res., vol. 11, pp. 1211–1220, 2019.
S. Chen, M. Yu, L. Ju, G. Wang, K. Qian, Y. Xiao, and X. Wang, The immune-related biomarker TEK inhibits the development of clear cell renal cell carcinoma (ccRCC) by regulating AKT phosphorylation, Cancer Cell Int., vol. 21, no. 1, p. 119, 2021.
Y. Zhu, L. Xu, J. Zhang, W. Xu, Y. Liu, H. Yin, T. Lv, H. An, L. Liu, and H. He, et al., Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3β/Snail signaling in renal cell carcinoma, Cancer Sci., vol. 104, no. 6, pp. 663–671, 2013.
P. Xi, Z. Zhang, Y. Liu, Y. Nie, B. Gong, J. Liu, H. Huang, Z. Liu, T. Sun, and W. Xie, Multidimensional comprehensive and integrated analysis of the potential function of TMEM25 in renal clear cell carcinoma with low expression status, Aging (Albany NY), vol. 16, no. 1, pp. 367–388, 2024.
W. Zhong, C. Huang, J. Lin, M. Zhu, H. Zhong, M. H. Chiang, H. S. Chiang, M. S. Hui, Y. Lin, and J. Huang, Development and validation of nine-rna binding protein signature predicting overall survival for kidney renal clear cell carcinoma, Front. Genet., vol. 11, p. 568192, 2020.
Z. Zhang, E. Lin, H. Zhuang, L. Xie, X. Feng, J. Liu, and Y. Yu, Construction of a novel gene-based model for prognosis prediction of clear cell renal cell carcinoma, Cancer Cell Int., vol. 20, p. 27, 2020.
Y. Zhan, R. Zhang, C. Li, X. Xu, K. Zhu, Z. Yang, J. Zheng, and Y. Guo, A microRNA-clinical prognosis model to predict the overall survival for kidney renal clear cell carcinoma, Cancer Med., vol. 10, no. 17, pp. 6128–6139, 2021.
V. Petrozza, A. Carbone, T. Bellissimo, N. Porta, G. Palleschi, A. L. Pastore, A. Di Carlo, C. Della Rocca, and F. Fazi, Oncogenic microRNAs characterization in clear cell renal cell carcinoma, Int. J. Mol. Sci., vol. 16, no. 12, pp. 29219–29225, 2015.
H. Tusong, N. Maolakuerban, J. Guan, M. Rexiati, W. G. Wang, B. Azhati, Y. Nuerrula, and Y. J. Wang, Functional analysis of serum microRNAs miR-21 and miR-106a in renal cell carcinoma, Cancer Biomark., vol. 18, no. 1, pp. 79–85, 2017.
Z. F. Jing, J. B. Bi, Z. Li, X. Liu, J. Li, Y. Zhu, X. T. Zhang, Z. Zhang, Z. Li, and C. Z. Kong, Inhibition of miR-34a-5p can rescue disruption of the p53-DAPK axis to suppress progression of clear cell renal cell carcinoma, Mol. Oncol., vol. 13, no. 10, pp. 2079–2097, 2019.
Y. Liu, H. Nie, Y. Zhang, N. Zhang, M. Han, H. Liu, D. Sun, X. Wu, X. Xiao, and X. Cao, MiR-224-5p targeting OCLN promotes the proliferation, migration, and invasion of clear cell renal cell carcinoma cells, Urol. Int., vol. 106, no. 11, pp. 1185–1194, 2022.
J. Zhou, P. Li, J. Feng, Q. Wu, and S. You, MiR-24-1-5p hinders malignant phenotypes of clear cell renal cell carcinoma by targeting SHOX2, Biochem. Genet., vol. 61, no. 5, pp. 2004–2019, 2023.
L. Guan, J. Tan, H. Li, and X. Jin, Biomarker identification in clear cell renal cell carcinoma based on miRNA-seq and digital gene expression-seq data, Gene, vol. 647, pp. 205–212, 2018.
S. Qin, X. Shi, C. Wang, P. Jin, and F. Ma, Transcription factor and miRNA interplays can manifest the survival of ccRCC patients, Cancers (Basel), vol. 11, no. 11, p. 1668, 2019.
M. Huang, T. Zhang, Z. Y. Yao, C. Xing, Q. Wu, Y. W. Liu, and X. L. Xing, MicroRNA related prognosis biomarkers from high throughput sequencing data of kidney renal clear cell carcinoma, BMC Med. Genomics, vol. 14, no. 1, p. 72, 2021.
M. Han, H. Yan, K. Yang, B. Fan, P. Liu, and H. Yang, Identification of biomarkers and construction of a microRNA-mRNA regulatory network for clear cell renal cell carcinoma using integrated bioinformatics analysis, PLoS One, vol. 16, no. 1, p. e0244394, 2021.
X. Zuo, C. Lu, Y. Zheng, D. Lai, D. Liu, G. Wan, C. Lu, and X. Gu, Effects of the targeted regulation of CCRK by miR-335-5p on the proliferation and tumorigenicity of human renal carcinoma cells, J. Oncol., vol. 2022, p. 2960050, 2022.
Q. Xing, J. Luan, S. Liu, L. Ma, and Y. Wang, Six RNA binding proteins (RBPs) related prognostic model predicts overall survival for clear cell renal cell carcinoma and is associated with immune infiltration, Bosn. J. Basic Med. Sci., vol. 22, no. 3, pp. 435–452, 2022.