GC is a relatively common digestive malignancy, especially in Asian countries. Many patients lose the opportunity for surgery because of the delayed diagnosis. The treatments for advanced GC mainly include chemotherapy and targeted therapy, but the efficacy remains poor. The molecular genetic landscape of GC includes gene mutations, transcriptional changes involving mRNAs and lncRNAs[12]. Many lncRNAs have been discovered in GC tissues, cells, gastric juice and plasma, and lncRNAs may act as potential biomarkers for early diagnosis and the evaluation of prognosis, therapeutic response, and chemotherapy resistance [13]. Furthermore, we can utilize public bioinformatics databases to explore the novel perspective of applying prognostic lncRNAs as biomarkers in GC.
It is well-known that GC is a multistep oncogenic process with characteristics of pathological and molecular heterogeneity. Prognostic-related lncRNA signatures are more reliable than single lncRNAs in prognosis prediction. As shown in Table 3, many lncRNA signatures have been reported in recent years. Cai et al. and Nie et al. identified many differentially expressed lncRNAs, but their models were difficult to implement in clinical practice [14, 15]. Although some studies showed signatures composed of fewer lncRNAs, the accuracy of the prognostic evaluation was not high [16, 17]. Moreover, some scholars have established models that can accurately predict prognosis, but they have not further explored the corresponding target genes [18, 19]. In this study, we established a prognostic signature that had good predictive ability and was an independent risk factor in GC. Compared to the traditional TNM staging system, the nomogram can accurately predict OS and be precisely applied in clinical practice.
Table 3
Comparison of existing prognostic signatures in GC
Databases | Methods | Signature | Symbols | Survival event | AUC value | References |
TCGA | LASSO Cox Univariate Cox | 3 | CYP4A22-AS1 AP000695.6 RP11-108M12.3 | OS | 0.737 | Cheng et al. 2018. |
TCGA | Univariate Cox MultivariateCox | 9 | ADAMTS9AS1 LINC01614, CYMP-AS1 OVAAL, LINC01210, LINC02408,FLJ42969LINC01775, LINC01446 | OS | 0.795 | Cai et al. 2019 |
GSE62254 GSE57303 | Robust likelihood- based survival LASSO Cox | 6 | lncRNA-IPW NCRNA00086 RP11-38P22.2 ERVH48-1 LOC158572 AC004080.17 | OS | 0.77 | Ma etal. 2019 |
TCGA | LASSO cox Univariable Cox MultivariateCox | 3 | AC007991.4 AC079385.3 AL109615.2 | OS | 0.751 | Zhang et al. 2020 |
TCGA | Univariable Cox MultivariateCox | 3 | OVAAL, FLJ16779 FAM230D | OS | 0.748 | Wang et al. 2020 |
TCGA GSE62254 | LASSO cox Univariable Cox MultivariateCox | 14 | ADAMTS9-AS2 FLG-AS1 RNF144A-AS1 LINC00922,C15orf54 ERVMER61-1 POU6F2-AS2 LINC01210,LINC00973 ERICH3-AS1 LINC00326, LINC01208 LINC00645, DSCR10 | OS | 0.737 | Nie et al. 2020 |
TCGA GSE62254 GSE15459 | Univariate Cox Multivariate Cox | 5 | LINC00205, TRHDE-AS1, OVAAL LINC00106,MIR100HG | OS DFS | 0.734 | Wu et al. 2021 |
Among the six lncRNAs, AC093850.2 and AC098973.2 are known as LINC01614 and LINC01980, respectively.AC093850.2 has been identified as a potential predictor of prognosis in many cancers, such as breast cancer, esophageal squamous cell carcinoma (ESCC), glioma, and osteosarcoma [20–23]. In the latest study, AC093850.2 was found to promote GC cell growth and migration [24], but the mechanism should be explored in GC. AC098973.2 may act as an oncogene in ESCC and hepatocellular carcinoma (HCC) [25, 26]. In addition, the LINC01980/miR-190a-5p/MYO5A pathway promotes the development of ESCC [25]. Previous research established a three-lncRNA prognostic signature including AP000695.6, but the value of AP000695.6 has not been further verified in clinical samples [27]. RP11-284F21.7 was evaluated in lung cancer cells [28]. RP4-584D14.7 was found in renal cell carcinoma cells [29]. In this study, these lncRNAs were identified from GC patients in the TCGA database. The expression levels of the two lncRNAs in tissue samples and cel lines were detected by qRT-PCR. Due to the limited tissue samples, we only verified the expression of two hub lncRNAs in GC tissues. The high expression levels of the two lncRNAs (AC098973.2 and RP11-284F21.7) were carried out in GC tissues and cell lines for the first time. However, a large number of clinical samples from multiple centers need to be assessed, and the specific regulatory mechanisms need to be deeply explored in GC.
Our study evaluated that the biological function of the signature components was related to the ECM. The current study showed that ECM and ECM-related components play an essential role in the occurrence and development of GC [30]. We found that the 24 target genes were mainly composed of ECM-related genes, such as SPARC, BGN, FBN1, SPP1, and FN1. Similarly, the pathways related to the signature included ECM-receptor interactions. The present study suggests that ECM targeting holds great clinical potential as an innovative and effective treatment for GC [31]. KEGG pathway analysis showed that these genes were rich in the Wnt signaling pathway and focal adhesion. Yang et al. revealed that LINC01133 inhibited progression and metastasis via the Wnt/β-catenin pathway in GC [32]. As dysregulation of the Wnt pathway has been observed in approximately 50% of GC tumors [33], the Wnt pathway might offer a new therapeutic target. Likewise, the CBP/β-catenin antagonist PRI-724 has been developed as a Wnt pathway inhibitor [34]. In addition, the integrins and growth factor receptors consisted of the focal adhesions through cytoplasmic signaling networks. Previous research has revealed that targeting focal adhesion proteins would be an effective mechanism of treatment regimens including chemotherapy, radiotherapy and novel molecular therapeutics [35]. Thus, the six-lncRNA signature has clinical potential as a pharmacological target.
IGFBP7, VCAN, and COL1A1 were closely related to prognosis in the study. Recent studies concluded that high expression of IGFBP7 was associated with poor survival in HCC [36], colon cancer [37], and GC [38]. C Rupp et al. provided evidence that IGFBP7 might selectively inhibit colon cancer metastasis through the suppression of epithelial-mesenchymal transition (EMT) [39]. Thus, further research on the pathogenesis and immune mechanism of IGFBP7 needs to be performed in GC. COL1A1 and VCAN are widely related to ECM-receptor interaction. COL1A1 is a member of the type I collagen family and is involved in breast cancer [40], HCC [41], ovarian cancer [42] and GC [43]. COL1A1 is closely correlated with cell invasion and metastasis based on the activation of the TGF-β signaling pathway [44]. VCAN is a chondroitin sulfate proteoglycan and it can provide hydration and a loose matrix during disease progression. Cheng et al. revealed that VCAN was upregulated and had an impact on the progression of GC [45]. Mohamed Salem found that high expression levels of VCAN mediated miR-590-3p and promoted the development of ovarian cancer [46]. Consequently, these target genes have important clinical application value.
Nevertheless, out study revealing a six-lncRNA signature has several limitations. First, we only obtained data from the TCGA, and more databases are required for further validation. Thus, we need large-scale cohorts to verify the prognostic signature in a multicenter prospective clinical study. Third, the six lncRNAs need to be further explored to determine their functions and underlying mechanisms. The six-lncRNA signature might provide new insight for individualized and precise treatment in GC patients.