To improve the survival time of GC patients, early diagnosis and treatment have been recognised as effective methods. Thus, the exploration of useful biomarkers for early diagnosis and positive management based on the mechanism of GC development is required. To date, several available biomarkers, such as CA-199, CA72-4, and CEA, are used. However, the sensitivity and specificity of those biomarkers are low. The first study of lncRNAs in GC has been reported in 1997 [29], with more research focused on the clinical value of lncRNAs in GC diagnosis. Exploration of dysregulated lncRNAs as biomarkers for GC diagnosis has several advantages: 1) lncRNAs can be detected and resist ribonuclease degradation in body fluids [30]; 2) expression of lncRNAs has temporal and tissue specificity [31]; 3) ectopic expression of lncRNAs is responsible for tumorigenesis [32, 33]. Therefore, investigation of lncRNAs might produce novel diagnostic and prognostic biomarkers for GC and help us understand the molecular mechanisms of GC development and progression.
To explore the potential role of lncRNAs in GC, the present study reviewed and analyzed published studies that reported differentially expressed lncRNAs between GC and normal tissue using microarray analysis. Since there was a substantial variety of reported data, for meta-analysis we retrieved articles reporting on the diagnostic value of lncRNAs. However, the results indicated that the data pooled from all studies showed marked heterogeneity that was most likely associated with specimen types as shown by meta-regression analysis. Subsequently, we performed a subgroup meta-analysis. Although it revealed that individual or specific lncRNA combinations could potentially serve as novel biomarkers for diagnosis of GC, the heterogeneity was still too high. Meanwhile, we found that the data from different research groups had significant differences in quality. Through GEPIA analysis, we validated eight lncRNAs with significant differences of expression in GC compared to normal tissue. To explore the potential function of these lncRNAs in GC, we utilised IPA analysis to investigate molecules interacting with these lncRNAs in gastrointestinal diseases. We used bioinformatics methods based on three datasets (GSE52149, GSE19826, and GSE79973) to identify DEGs in GC. Then results for lncRNAs and DEGs were pooled into the Venn diagram to identify two genes (IGF2BP3 and FOLR1), which might be regulated by altered lncRNAs in GC samples. Finally, we utilised GEPIA and Kaplan Meier plotter analysis to validate that IGF2BP3 and FOLR1 both changed significantly and correlated with worse survival time in GC patients. Nevertheless, further research is still required to investigate mechanisms underlying these observations that might provide new effective treatments and improve outcomes for GC patients.
Insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3), also known as IMP3, belongs to a conserved IGF2 mRNA-binding protein family. It has been first recognised in 1997, due to its high expression in pancreatic carcinoma [34]. Subsequently, IGF2BP3 has been found to be overexpressed in various tumors [35–38]. Moreover, it has been demonstrated to modulate tumor cell fate by promoting tumor growth [39], cell proliferation [2], drug-resistance [40], and invasiveness [41]. The expression of IGF2BP3 has been shown to correlate with prognosis and metastasis of human cancer. Another study has shown that H19, PEG10, and IGF2BP3 promote expression of each other and that down-regulation of their expression can decrease cell proliferation, anchorage-independent growth, invasion, and chemoresistance in GC [42].
Folate receptor 1 (FOLR1) is a membrane-bound protein with a high affinity to folate that binds and transports folate with physiological levels into cells. Folate, one of the crucial components of cell metabolism and DNA synthesis and repair, is a requirement for the rapid division of cancer cells [43]. A higher expression of FOLR1 has been found in specific epithelial-derived malignant tumors compared to normal tissues [44] and has been illustrated to positively correlate with tumor grade and stage [43]. During early carcinogenesis, FOLR1 may promote cells to increase folate uptake and repair DNA damage [45]. Recently, FOLR1 has been confirmed as a potential target for immunotherapy with chimeric antigen receptor (CAR) T cell in GC [46]. However, at this time the role of FOLR1 in etiology and progression of GC is not fully understood.
Numerous studies have proven lncRNAs play a critical role in DEGs function in GC. However, as a regulator for various signaling pathways, very few studies report on the mechanism underlying these changes in lncRNAs and DEGs in GC. Therefore, the results of the present study might provide useful information that can guide researchers in studies of mechanisms involved and explorations of novel potential candidates as biomarkers for diagnosis of GC.