Recently, RBPs were becoming progressovely more important by the profoung study conducted on its roles in various cancers and increasingly regarded as crucial factors in posttranscriptional regulation 18–20. The dysfunction of posttranscriptional regulation that were related with the origination of cancer could enhance the function mutations of oncogenes and depresse mutations of tumor suppressor 21; 22. To the best of our knowledge, this was the first study focused on the role of RBPs in the progression and prognosis of KIRP. Here, we integrated RNA sequencing data of KIRP from the TCGA database and sorted out differentially expressed RBPs between tumor and normal patients. We further coducted GO and KEGG enrichment analyses and established PPI network for these RBPs. Moreover, we constructed a OS-predictve model for predicting the prognosis of KIRP patients and performed ROC analyses to evaluate the feasibility of our model. Subsequently, GSEA was conducted to figure out the biological functions of two selected RBPs.
As for the results of biological functions and pathway enrichment analyses, DEGs were enriched in ribosome and posttranscriptional modification pathways, such as RNA splicing, RNA transport, spliceosome and translation. Large numbers of studies in recent years have reported that aberrant RNA modification and RNA metabolism were of great value in various cancers 23 24. Alternative RNA splicing events, which were probably adjusted by RBPs, were reported prevalent in liver cancer and affected tumorigenesis in metabolism-related pathways by investigations conducted by Li, S research team 25. In addition, the manipulation of alternative splicing was proved to be a new method to suppress tumorigenesis in glioblastoma by Mogilevsky and their colleagues 26. Will research team discovered that spliceosome was consist of five snRNPs and numerous proteins which catalyze pre-mRNA splicing 27. Varialbe levels of RNA and protein components influenced splice cite and research conducted by Dvinge and their partners showed that the spliceosome shaped the global transcriptome of breast cancer 28. In ovarian cancers, Li et al. found that spliceosome could to promote proliferation and invasion by the upregulation of associate factor 29. Previous studies have shown the relationship and possible mechanisms between RBPs and spliceosome 30 31.
Subsequently, through the application of univariate Cox regression analysis, random survival forest analysis, multivariate Cox analysis and Kaplan–Meier test, we determine six RBP-coding genes: SNRPN, RRS1, INTS8, RBPMS2, IGF2BP3 and PIH1D2. The risk score model was then constructed to predict the prognosis of patients. It was noteworthy that patients with high risk scores tend to have worse prognosis, implying that individual therapeutic schedules should be taken into consideration. The ROC curve of risk score model revealed that the six-RBP signature was comparatively reliable in predicting prognosis with the AUC values of 0.87 and 0.75 at 3 years as well as 0.78 and 0.69 at 5 years in training set and test set. A nomogram comprised independent prognostic factor and six-RBP signature was established to assist the prediction of 3-year and 5-year overall survival in clinical treatments.
In addition, we performed GSEA on SNRPN and RRS1 since they were concurrently parts of subnetwork of PPI. SNRPN (small nuclear ribonucleoprotein polypeptide N) was widely regarded as a spliceosome component 32. As to the results of GSEA, low-expression SNRPN was enriched in E2F targets. E2F was a family of transcription factors and had various functions such as controlling the cell cycle, regulating transcription and apoptosis 33. More importantly, E2F targets were reported to play significant roles in several cancers. For example, Park research team announced that E2F targets were activated by EPEL to promote cell proliferation of lung cancer 34. Meanwhile, Sun and their colleagues made a research on the roles of E2Fs in breast cancer and considered E2F4 and 6 as biomarkers, together with E2F1, 3, 5, 7 and 8 as potential targets of therapy 35. The inhibition of E2F downregulated the ability of BRD4 binding with the promoter of miR-106b-5p and inhibited its transcription which resulted in the cellular senescence of gastric cancer cells were investigated by Dong, X team 36. High-expression RRS1 was enriched mainly in mTORC1 signaling. The mTORC1 signaling pathway was a classical pathway connecting to tumorigenesis 37. According to studies of He et al. and Guigon et al., the growth of pancreatic cancer and thyroid cancer were inhibited by the suppression of mTORC1 signaling 38 39. Experiments on the the interaction mechanism of TRAF6 and p62 were carried on by Linares and their colleagues. Results revealed the importance for lung cancer cell proliferation through the activation of mTORC1 40. Last but not least, we made a prediction of potential small molecular drugs which may be of therapeutic benefits for KIRP patients and had a certain degree of reliability.
Overall, our study dissected the relationship between RBPs and KIRP for the first time and proposed a novel direction for exploring the tumorigenesis and prognosis of KIRP. We determined 6 RBPs which were linked with prognosis, constructed a reliable prognostic OS-predictive model and speculated three potentially useful drugs. The six RBPs could act as potential therapeutic targets of KIRP and contribute to the development of clinical treatment. Nevertheless, our study had several limitations. First, our prognostic model was only constructed on the TCGA database and lack of clinical data from the GEO database to evaluate. Meanwhile, the lack of clinical characteristics of clinical data from TCGA may decrease the credibility of our research. Moreover, our results were based on RNA sequencing, patients had the possiblity to exhibit inter-individual heterogeneity. Finally, prospective clinical studies had the necessarity to condut before our 6-RBP prognostic model put into use.