As one of the most common malignant tumors threatening human health, GC has significant limitations in the treatment of advanced GC, and many problems have not been solved [26]. Therefore, it is critical to screen for new biomarkers or the hub genes for therapeutic targets of early GC. In this study, 4892 DEGs were screened. The results of GO and KEGG analyses showed that these DEGs were significantly associated with extracellular matrix organization, DNA replication, cell cycle, and p53 signaling pathway. The cell cycle is often dysregulated during the formation of many tumors and targeted regulation of cancer cell cycle therapy is a potential treatment for cancer [27, 28]. Thus, studying the cell cycle pathway may improve the understanding of GC carcinogenesis mechanisms and treatment options. DNA replication is closely related to the cell cycle. DNA replication, including incomplete, erroneous, or untimely replication, may cause mutations, chromosomal poly- or aneuploidy along with gene copy number variation, and these variations may lead to cancer [29]. Extracellular matrix (ECM) is involved in the regulation of cancer development and plays an important role in tumor metastasis [30]. The p53 signaling pathway is a typical cancer signaling pathway, the presence of p53 is required for DNA-damaged cells to arrest, repair, as well as re-enter the cell cycle [31]. Therefore, we may think that these DEGs may play a role in the progression of GC, and may affect prognosis by regulating the p53 signaling pathway, resulting in a poor prognosis of GC.
WGCNA identified gene co-expression modules associated with GC progression. A total of 6 modules were identified, among which the genes in blue and turquoise modules were significantly related to GC (Tumor_Normal). Then, the genes in blue and turquoise modules were screened and verified, and 19 hub genes were screened by survival analysis and differential expression analysis. These results indicate that the verified hub genes may have a promising future in the diagnosis and treatment of GC.
At present, the early detection of cancer has important clinical significance and value, which challenges the frontier of early detection of cancer. Therefore, we investigated the differential expression of these 19 hub genes between different pathological stages of GC and normal tissues. Analysis showed that the expression levels of ASF1B, EPCAM, FAM83H and CEP55 in early GC were significantly higher than those in normal tissues, and the expression levels of the other 14 hub genes were lower in early GC, suggesting that the hub genes may have important clinical significance in the early diagnosis of GC.
Many of the 19 hub genes we identified have previously been reported to be associated with cancer. A study reports that high expression of ASF1B is associated with the increase of disease progression and metastasis rate of breast cancer [32]. Researchers have demonstrated that DPT is related to cell adhesion and invasiveness, and plays an important role in regulating the invasion and metastasis of oral squamous cell carcinoma [33]. As for ZBTB16, MAMDC2, TCEAL2 and TMEM100, four studies have reported that they can inhibit the activity, proliferation or metastasis of tumor cells, including gallbladder cancer, breast cancer, renal cell carcinoma and nonsmall cell lung cancer [34–37]. PDZD4 and ADHFE1 have been proved to be associated with synovial sarcoma and colorectal cancer cell proliferation, respectively [38, 39]. Two studies have reported that LIMS2 and LMOD1 can promote the migration of GC cells [40, 41]. As for WISP2, researchers have demonstrated that it has a bidirectional regulatory effect on tumor cells, with WISP2 overexpression inhibiting the growth of esophageal cancer cells and its absence inhibiting the proliferation of tumor cells in ovarian cancer [42, 43]. In particular, LIMS2, LMOD1, TCEAL2, TMEM100 and ZBTB16 have been reported to play important roles in the development of GC [40, 41, 44–46]. These results suggest that the hub gene we screened may have an important potential role in GC and may be acted as a biomarker for the early screening of GC.
Early detection, diagnosis and treatment of cancer can not only significantly improve the survival rate, but also have a higher quality of life. This study advances our understanding of the early diagnosis of GC. These hub genes may be used as biomarkers and potential therapeutic targets for early GC, and their discovery has important clinical significance for the early diagnosis, treatment and survival prognosis of GC patients. However, our study still has some shortcomings and lacks further molecular biology experiments to confirm the function of these hub genes in GC.