>50% of KIRCs were currently detected incidentally through frequent non-invasive radiological techniques because of the classical triad of flank pain, gross haematuria and palpable abdominal unconspicuous4,which showed early KIRCs were discovered difficultly. MicroRNAs (miRNAs) can exist highly and stably in many biological fluids [e.g. serum, urine] and be used for biomarkers for detecting tumor formation.11In this investigation, by RT-qPCR and the 2−△△Cq method to assess between serum samples from NCs and KIRCs for twice, we observed miR-1-3p, miR-129-5p, miR-146b-5p, miR-187-3p and miR-200a-3p may be biomarkers for detecting KIRC genesis. Also, we discovered that a biomarker panel consisting of miR-1-3p, miR-129-5p, and miR-146b-5p may be the most effective combination for identifying KIRC. Using the GEPIA database, it has been determined that CREB5 is likely to be one of the common target genes for the miR-1-3p, miR-129-5p, and miR-146b-5p. By Kaplan-Meier survival analysis, 506 KIRC patients’ survival rate was compared and the result shown the overexpression of miR-146b-5p hinted KIRC patients had worse prognosis.
When compared to NCs, miR-1-3p levels were lower in KIRC serum; this led researchers to hypothesize that miR-1-3p may inhibit the expansion of KIRC.
miR-1-3p was found to have an inhibitory effect in a variety of malignancies, including hepatocellular carcinoma17, prostate cancer18 and bladder cancer.19
Recently, a lncRNA-miRNA-mRNA regulatory circuitry was put forward that miRNAs could be competitively inhibited by long non-coding RNA (lncRNAs) as competing endogenous RNAs (ceRNAs) and can't control mRNA regularly.20Overexpression of LINC00242 in gastric cancer cells has the impact of sponging the expression of miR-1-3p, which in turn adversely regulates G6PD expression. This has the consequence of inhibiting both tumor proliferation and aerobic glycolysis.21When it comes to hepatic carcinogenesis, the LncRNA known as TUG1 has the ability to adsorb miR-1-3p, which promotes the expression of IGF1 and the proliferation of tumors.22 In oesophageal squamous cell carcinoma, LncRNA LINC01518 knockdown to upregulate miR-1-3p inhibited tumorigenicity.23A circRNA -miRNA regulatory circuitry also had been proposed that Circular RNAs (circRNA) may impose effects by sponging miRNA, inevitably leading to the derepression of miRNA targets in the long run.24 Glycosyltransferase C1GALT1 was found to be controlled in bladder cancer (BLCA) by the cHP1BP3 (circRNA produced from HP1BP3) -miR-1-3p axis, which was repressed and decreased the migratory ability and proliferation of BLCA cells in vitro and in vivo by changing target glycoproteins.25
Similarly, compared with NCs, miR-129-5p was also down-regulate in KIRC serum. Recent research has shown that the microRNA known as miR-129-5p has an anti-tumor effect in KIRC.26With this specific downregulation of SPN gene expression, miR-129-5p was able to limit the progression of KIRC.26
Docetaxel resistance was promoted in prostate cancer by down-regulating CAMK2N1 expression, which was connected with miR-129-5p, which was associated with tumor drug resistance (mRNA).27miR-129-5p is an essential component of both the lncRNA-miRNA-mRNA regulation circuitry as well as the circRNA-miRNA regulatory circuitry. LncARSR acted as a sponge for miR-129-5p, which led to promote the metastasis and proliferation of bladder cancer. This was accomplished by elevating the expression of Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4).28 The miR-129-5p that was controlled by the Circ 0007841 gene had an effect on the proliferation and metastasis of multiple myeloma.29
There was a significant relationship between miR-146b-5p and the prognosis.
miR-146b-5p may influence the expression of the BRCA1 gene to govern the progression of triple negative sporadic breast cancers.30Moreover, miR-146b-5p has the potential to be employed as one of the good predictive criteria for triple negative breast cancer relapse.31 In our study, the overexpression of miR-146b-5p hinted KIRC patients had worse prognosis. A panel of miRNAs had been applied in some tumors such as hepatocellular carcinoma32 and colorectal cancer33.The blood expression of three miRNAs (miR-1-3p, miR-129-5p, and miR-146b-5p) have the potential to serve as a reliable biomarker for the diagnosis of KIRC (Fig. 3).
CREB5 could be considered as potential target gene of KIRC in our study. Although CREB5 has not be studied in KIRC, but a lot of researches for CREB5 in other tumors had been reported. In Metastatic castration-resistant prostate cancers, the combine of CREB5 and FOXA1 promoted epithelial to mesenchymal transition (EMT) signaling in AR-positive-resistant cells.34,35 What’s more, CREB5 directly activates mesenchymal-epithelial transition (MET) to promote the invasiveness and metastasis of colorectal cancer36 and regulates vasculogenic mimicry in breast cancer cells.37
Some studies on serum biomarkers of RCC had been published that researchers found panels including multi-miRNAs could be serum biomarker for RCC diagnosis. During the studies, the AUC of a four-miRNA panel for RCC diagnosis, containing miR-1-3p, miR-155-5p, miR-200b-3p, and miR-224-5p, was 0.903 (95% CI: 0.847–0.944; p < 0.001; sensitivity = 75.61%, specificity = 93.67%)38. Similarly, the AUC of another four-miRNA panel, containing miR-18a-5p, miR-138-5p miR-141-3p, and miR-181b-5p, was 0.908 (95% CI: 0.852–0.948; sensitivity = 80.77%, specificity = 88.89%)39. Our study reported that the AUC of a three-miRNA panel for KIRC diagnosis, including miR-1-3p, miR-129-5p and miR-146b-5p, was 0.895(95% CI: 0.848 to 0.942; sensitivity = 89.30%, specificity = 76.19%). Compared with previous studies, our study focused on KIRC not RCC. However, KIRC accounted for approximately 75% of all cases of RCC3. The KIRC’ mi-RNAs were highly correlated with RCC. miR-1-3p simultaneously emerged in the panel of RCC and KIRC which probably shown the importance in the evolution of RCC, but other mi-RNAs didn’t simultaneously emerge in RCC and KIRC which indicated mi-RNAs played different roles in different RCC subtypes. Therefore, the functions of mi-RNAs in different RCC subtypes should be researched separately. Some mi-RNAs may be important roles in different RCC subtypes. A defect that the number of samples for RCC and KIRC was small emerged in our study and previous studies, so a bigger number of samples should be collected. In a word, the object of previous studies was RCC, but the object of our study was KIRC. miR-1-3p was potential biomarker for RCC and KIRC. A big number of samples was be collected.