The lack of markers for detection limits the prevention and treatment of GC, leading to a low survival rate for patients [29]. Although there is very wide global variation, the overall five-year survival rate of patients with GC is approximately 20-30% in most countries [30]. The blocking of GC can reduce the side effects of unnecessary palliative radiotherapy and chemotherapy and increase the survival rate of GC patients. To identify GC, we must explore the potential biomarkers useful for its diagnosis of GC. The miRNA expression in GC tissue samples may have an important role for miRNAs in tumorigenesis and progression of the disease and differentially expressed miRNAs correlate with the pathological type of GC [31,32]. miRNA in plasma could serve as potential biomarker in detection of GC [31,33]. Several studies discovered the identical trend of alteration between tissue miRNAs and plasma miRNAs [34,35]. This suggests that plasma biomarkers may be an alternative to tissue biomarkers. Thus, it would be more clinical significance, if we can discern the miRNAs that are common differentially expressed in GC tissue and plasma.
Shin et al., proposed three miRNA signatures (miR-627, miR-629, and miR-652) as potential diagnostic markers of GC [36]. Li et al., revealed that miR-199a-3p in plasma may be considered as a potential diagnostic biomarker for GC detection [37]. In this study, we analyzed sequencing data for miRNAs in 389 GC samples and 41 adjacent non-tumor tissues from TCGA. Altered miRNA expression patterns were identified between GC and non-tumor tissues, implying a potential diagnostic role for miRNAs in GC. As a result of the hierarchical clustering analysis, 111 DE miRNAs were identified. Furthermore, 13 DE miRNAs of diagnostic value were selected by performing ROC analysis. Among the 13 DE miRNAs, we identified that the expression of miR-143-3p was significantly downregulated in GC plasma compared to healthy subjects by high-throughput small RNA profiling. miR-143-3p is well-conserved in vertebrates and is known to be a potential regulator of tumor growth [38,39]. Additionally, miR-143-3p has been reported to inhibit the development of ovarian and breast cancer [39,40]. miR-143-3p may serve as a diagnostic marker of osteosarcoma, chondrosarcoma, and bladder cancer [41-43]. Furthermore, evaluating the diagnostic accuracy of miRNA based on GC tissue confirmed that miR-143-3p has a high diagnostic value as a single molecule [32]. Therefore, based on previous studies and our findings, we have demonstrated that miR-143-3p may be valuable as a diagnostic biomarker for GC. When we validated the diagnostic value with 21 GC and 17 healthy controls, the level of miR-143-3p was significantly downregulated in GC patients. This finding needs to validate more with large numbers of patients.
In the present study, we identified a stronger molecular biomarker for GC by targeting miRNAs identically downregulated in two profile datasets. The miRNA–mRNA interaction network was constructed, resulting in the identification of miR-143-3p related 228 target genes. To investigate their functional levels, we analyzed the GO functions and KEGG pathways. A PPI network was constructed to identify the top 10 hub genes. SMAD3, TNF, MMP2, MMP9, CTGF, CD44 and AKT1 are associated with atherosclerosis [44-50]. Gastric cancer and atherosclerosis are known to share many etiological and mechanistical processes, as well as several important molecular pathways [51]. The GO analysis revealed that biological processes were significantly enriched for GC development. The extracellular matrix (ECM) is an interconnected macromolecular structure that contributes to cell migration and cancer development [52,53]. Moreira et al., described how the disruption of the ECM organization impairs GC function and tissue structure, eventually leading to the progression of gastric cancer [54]. Through KEGG analysis, we identified pathways significant in the pathogenesis of GC, such as pathways in cancer, PI3K–Akt signaling, proteoglycans in cancer, and microRNAs in cancer. PI3K–Akt signaling may play a significant role in potential therapeutic targets for gastric cancer [55,56]. Ye et al., proved that inhibiting PI3K signaling reduced the expression of p-AKT and MMP2, thereby suppressing the proliferative activities and metastatic capabilities of gastric cancer cells [57]. Our study shows crucial molecular pathways and provides insights into potential targets for GC. The results of our analyses are greatly significant for the investigation of the role of miR-143-3p and related target genes in the progression of GC. However, the conclusions of our study need to be further evaluated with a larger dataset.
Collectively, our study suggests that hsa-miR-143-3p represents a potential biomarker for the diagnosis of GC, with the potential to play a significant role through the pathways involved in GC progression. Nevertheless, its clinical application warrants further research.