In China, CRC has more than 376,000 new cases and 191,000 deaths every year [10]. And with the development of China's economy as well as the westernization of people's diet and lifestyle, the incidence of CRC is increasing year by year in China [11].Therefore, people should be diagnosed and treated early, which is the most effective way to reduce the incidence and mortality. In our research, the published data in the GEO database was conducted to analyze CRC samples comprehensively. And finally 7 biomarkers that was independent of clinicopathological factors for Overall survival rate in CRC were screened out.
First, we extracted DEGs from the GSE71187 data set in the GEO database. By setting thresholds, DEGs were divided into two types of genes, up-regulated and down-regulated. Through the visual mapping, the enrichment analysis of GO terms and KEGG was carried out on the two types of genes. We can comprehend better the occurrence and development mechanism of CRC based on the enrichment analysis. Next, we constructed the PPI network of DEGs and identified the constructed network by applying the MOCOD method, and finally selected six hub modules. By calculating the median expression value of 86 genes in 6 hub modules, the patients in the data set were divided into two types, high-expression group and low‐expression group. Through the overall survival analysis of the patients, the results showed that the P value of 11 module genes was significant. Ultimately, univariate and multivariable Cox regression analysis was utilized these 11 genes. The results demonstrated that 7 genes (NOC4L, MYBBP1A, CXCL3, TLR4, GHDC, LRG1, BCL3) had independent prognostic capabilities.
Human Nucleolar complex associated 4 homolog (Noc4L) is ribosomal biogenesis factor. It is not expressed equally in all tissues, but preferentially expressed in oocytes, testes and lymphoid organs. It plays a key role in early embryonic development. Wild et al confirmed that Noc4L was important for mammalian ribosomal biogenesis in HeLa cells [12].
MYB binding protein 1A (MYBBP1A) is a nucleolar transcriptional regulator and it is considered as a potential new tumor suppressor gene [13]. MYBBP1A was originally discovered to interact with the c-MYB oncogene product [14, 15]. Studies have shown that its expression has a certain correlation with cancers such as head and neck squamous cell carcinoma [16], kidney cancer [13], liver cancer [15] and breast cancer [17]. Xu et al. analyzed the human protein atlas database by integrating the prognosis of The Cancer Genome Atlas data and showed that MYBBP1A might be a good prognostic marker for pancreatic cancer, but it was disadvantageous in kidney cancer, thyroid cancer and melanoma [15]. In the study of CRC, it was demonstrated that the basic p53 level and proliferation was significantly rescued by silencing MYBBP1A in the PURPL-deficient cells. Therefore, it was indicated that MYBBP1A mediated the role of PURPL in regulating p53 in CRC cells [18].
C-X-C motif chemokine ligand 3 (CXCL3) is a member of the CXC chemokine family, and its expression is associated with various cancers, such as liver cancer [19], gastric cancer [20], breast cancer [21], prostate cancer[22], and non-small cell cancer [23]. Meanwhile, some scholars have explored CXCL3 in the CRC, and their findings consistently reveal that the expression of CXCL3 in cancer tissues is significantly higher than that in normal tissues [24, 25]. The research indicated that there was no significant difference in CXCL3 expression between non-metastatic and low metastatic colon cancer cells compared with highly metastatic colon cancer cells [26]. Farquharson et al. demonstrated that insulin and adiponectin could participate in the development of colon cancer by regulating CXCL3 [27].
Toll-like receptors (TLR) protein is a type I integrated transmembrane glycoprotein, and TLR4 is a member of this family [28]. TLR4 expression drives tumorigenesis in CRC [29] and the expression of TLR4 in CRC patients is associated with high tumor recurrence rate, which implies the important prognostic role of TLR4 in the prognosis of CRC [30]. The genetic polymorphism of TLR4 is also associated with colon cancer [31]. In addition, the combination of TLR4 and HA can promote the proliferation of colon cancer and inhibit spontaneous apoptosis [29]. More interestingly, many miRNAs have been involved in the carcinogenesis process by regulating TLR4 signaling pathways, such as miR-203 and miR-148a [32, 33]. Yan et al. revealed that MiR-6869-5p inhibited cell proliferation and inflammatory cytokine production by directly targeting TLR4 to mediate TNF-α and IL-6 in CRC cells. This indicates that the protective effect of miR-6869-5p on CRC depends on the TLR4 /NF-κB signaling pathway [34].
Leucine-rich alpha-2-glycoprotein 1 (LRG1) is a member of the leucine-rich repeat sequence family [35]. It is a secreted glycoprotein that can participate in immune response, cell proliferation, cell migration, apoptosis and neovascularization [36]. LRG1 is overexpressed in several types of cancer, including pancreatic cancer [37], bladder cancer [38], ovarian cancer [39] and biliary tract cancer [40]. In CRC, the expression of LRG1 is significantly increased compared to normal tissues. And knocking down LRG1 can significantly reduce the migration and invasion of CRC cells. Zhang et al. pointed out that LRG1 was a new inducer of epithelial-to-mesenchymal transition and a potential enhancer of CRC metastasis potential. Moreover, they also proved that the expression level of LRG1 was positively correlated with deeper infiltration depth and lymphatic metastasis. These results indicate that LRG1 may be involved in the occurrence and development of CRC [36]. According to the report, plasma LRG1 levels in CRC patients were higher than adenomatous polyps [41]. The serum LRG1 expression levels was used to distinguish colon cancer patients from healthy controls in a non-invasive manner and predict PFS of patients [42]. These results indicate that LRG1 may be a reliable biomarker for CRC diagnosis. However, the biological mechanism of GDHC remains unclear in solid tumors, maybe it is a potential tumor marker of CRC.
B cell leukemia/lymphoma 3 (Bcl3) is a phosphoprotein and is present in many cancer cells [43]. It plays a decisive role in promoting cell migration [44]. Bcl3 is abnormally expressed in several types of solid tumors, such as breast [45], endometrial [46], colorectal [47], nasal atrial [48], cervical [49] and ovarian cancer [50]. Bcl-3 nuclear expression is negatively correlated with the survival of CRC patients [47]. Legge et al. demonstrated that BCL-3 enhanced β-catenin/TCF-mediated signaling in CRC for the first time. BCL-3 selectively regulated the transcription of intestinal stem cell genes and Wnt targeting leucine rich repeat containing G protein-coupled receptor 5 (LRG5) and achaete-scute family bHLH transcription factor 2 (ASCL2), thereby promoting the cancer stem cells phenotype. Furthermore, they proposed that BCL-3 played a driving role in stem cell phenotype in CRC, which might promote the plasticity and therapeutic resistance of tumor cells [51].