An estimated 10–20% of all renal cell cancers are characterized by papillary renal cell carcinoma (PRCC), which is the second most common histological type of renal cell carcinoma. It has been remarkable to make rapid progress in explaining the molecular basis of this type of neoplasm in recent years. It is, however, still not possible to provide a reliable molecular biomarker for detecting pRCC presence and grade of malignancy in daily clinical practice(27). In advanced stages, late diagnosis of this cancer has resulted in treatment failures and reduced survival rates (28). Consequently, it is becoming increasingly important to find diagnostic biomarkers that can be used to detect early-stage cancer and prevent it from progressing. This study aimed to develop diagnostic biomarkers for PRCC which can be used either alone or combined with other diagnostic biomarkers. Based on the results of the analysis listed in Table 3, ten genes were selected for further analysis, six of which showed upregulation and four showed downregulation, and then roc curves were drawn for three genes, BCL11A, NTN5, and OGN.
It has been rare to report the role of BCL11A (B-cell lymphoma/leukemia 11A) in malignant solid tumors, but overexpression of BCL11A has been detected in some malignant solid tumors, suggesting that this gene may be a valuable diagnostic and prognostic tool for these tumors(29). In LSCC (laryngeal squamous cell carcinoma) tissues, high levels of BCL11A were found and were correlated with advanced lymphatic metastasis stages with poor prognoses. It has been shown that overexpression of BCL11A increases LSCC proliferation in vitro and in vivo. However, overexpression also causes high levels of MDM2 expression in LSCC cells, which interferes with the activity of p53(30). Amplification of BCL11A has also been demonstrated in lung squamous cell cancers (SCC), with the highest concentration of amplification found in samples from NSCLC (non-small cell lung cancer) without metastases. The expression of BCL11A was much greater in patients with early-stage cancer, suggesting that activation of the BCL11A proto-oncogene might occur at an early stage in lung cancer. Thus, BCL11A may play a role in diagnosing and predicting the prognosis of patients with lung cancer, particularly those with early-stage lung squamous carcinoma (31, 32). According to research, BCL11A expression levels decreased with increasing histological malignancy in breast cancer cases as well as cell lines. It was also negatively correlated with the size of primary tumors. The expression of BCL11A in BC that did not express estrogen or progesterone receptors as well as triple-negative cases was significantly lower. Therefore, it is likely that BCL11A is downregulated during the process of cancer occurrence(33). Additionally, in another study, BCL11A and SOX11 proteins were observed to have a significant positive correlation in the blood, suggesting that the two proteins may be regulated by the same pathway(34). A group of genes known as SOX genes have been implicated in the development of the kidney. In the early kidney anlagen, SOX11 is expressed at a level of both mesenchymal and epithelial expression. SOX11 directly binds and regulates a locus control region of the protocadherin B cluster on a molecular level. SOX11 is restricted to the intermediate segment of the developing nephron as it is necessary for the elongation of Henle's loop during the later stages of kidney development (35, 36). A number of other members of the SOX family, such as SOX6, SOX12 and SOX2, have also been shown to be associated with clinicopathological features, and may provide an advantageous prognostic biomarker for ccRCC patients (37, 38). As with many genes, BCL11A is regulated in part by miRNAs, and the let-7 family of miRNAs seems to affect BCL11A expression (39). Let-7 miRNAs play an important role in cell cycle control, differentiation, and apoptosis, and are widely considered tumor suppressors (40). Let-7 family members were found in abundance in urine cell-free supernatants of patients with ccRCC, and let-7a outperformed the other miRNAs, and may be a promising non-invasive biomarker for the detection of ccRCC(41).
Netrins are a family of highly conserved proteins that, in conjunction with semaphorins, slits, and ephrins, serve as neuronal guidance cues (42). In the beginning, these substances were known to play an important role in the development of the central nervous system, but over the last decade, they have been shown to participate in many other processes beyond central nervous system development, including a pivotal role in the development of cancer(43). There is a correlation between mutations of members of the Netrin family and cancer genetic characteristics, which suggests that these mutations may serve as potential biomarkers for prognosis and diagnosis. According to the studies, tumor mutations in members of the Netrin family show unique distribution patterns correlated with cancer type, protein structure, and ethnicity (44). A study conducted in individuals with inflammatory bowel disease demonstrated that NTN1 is upregulated in fibroblasts associated with colorectal cancer and that this promotes cancer cell stemness, thereby enhancing cancer cell progression (45, 46). Moreover, NTN1 has also been associated with the occurrence, development, survival and clinical parameters of kidney cancer and non-small cell lung cancer (44, 47, 48). A number of clinical parameters, such as survival rates and clinical parameters, are associated with the expression or methylation of NTNG1 and NTNG2. Furthermore, netrins are also altered by epigenetic and transcriptional factors in pan-cancer, which are associated with the activation of the EMT pathway (44). Furthermore, a study found that NTN1/3/4/G1 were significantly downregulated and NTN5/G2 were significantly upregulated in ccRCC tissues compared to normal renal tissues, suggesting that Netrin family members may be promising biomarkers for the detection of ccRCC (49). Among the netrins, NTN-5 (NTN5) is the most recently discovered and has received little attention thus far. It is expressed in neuroproliferative zones and is related to migration pathways in the adult brain(50). For the first time in this study, an increase in NTN5 expression was detected in PRCC and, based on the ROC curve, it can serve as a diagnostic biomarker for the diagnosis of this disease.
A wide range of cells secrete small leucine-rich proteoglycans (SLRPs), which are involved in a variety of processes. These processes include protein-protein interactions, signal transduction, cell adhesion, and DNA repair(51). In addition to their ability to bind collagen, the SLRP family also performs outside-in signaling (52). In addition to being one of the SLRPs, osteoglycin (OGN) is a member of the family of extracellular proteoglycans, which have several leucine-rich repeats, just like other members of the family. In addition to binding collagen and several growth factors, OGN may also be involved in remodeling the extracellular matrix (ECM). EGFRs (epidermal growth factor receptors) and IGFs (insulin growth factor receptors) are among the receptors(53). Many cancer cell lines lack the expression of OGN, suggesting that it may serve as a tumor suppressor gene in the development of cancer (54). Both ECRG4 and OGN function as tumor suppressors in the bladder, with ECRG4 overexpression inhibiting NF-kB signaling and promoting NFIC/OGN signaling in bladder cancer cells(55). OGN expression is associated with increased survival and decreased recurrence of colorectal cancer. OGN also suppresses the EGFR/AKT/Zeb-1 axis, reversing epithelial to mesenchymal transition (EMT)(56). However, elevated expression of OGN is associated with the EMT process and shorter overall survival in ovarian carcinoma tissues (57). In another study in breast cancer, OGN levels were significantly reduced in breast cancer tissue, and overexpression of OGN significantly inhibited cell proliferation, migration and invasion, and reversed EMT phenotypic changes. Furthermore, OGN's tumor suppressor activity in BC is demonstrated to be mediated by its effect on the PI3K/AKT/mTOR pathways(58). A significant reduction in OGN expression was observed in gastric cancer tissues, and a decrease in OGN expression was associated with more lymph node metastasis and poor differentiation status, both indications that a cancer has advanced. These results suggest that OGN downregulation might contribute to the progression of gastric cancer and could be utilized for the diagnosis and monitoring of cancer(53). A study investigated proteomics for diagnostic biomarkers of laryngeal cancer, and four differential proteins (PFN1, NCL, CNDP2 and OGN) with expressional changes were selected to test for differential expressions. Several of the four proteins, or some of them, were shown to be potential biomarkers for detection or therapeutic targets of human laryngeal carcinoma(59). As a result, based on the role of OGN in cancer and its potential as a biomarker, in this study, the role of this gene in PRCC has been shown for the first time, and based on the rock curve, it is possible for it to be used alone or in combination with two other genes, BCL11A and NTN5, to detect this disease.