Identification of novel key regulatory lncRNAs in gastric adenocarcinoma

Background Stomach adenocarcinoma (STAD) is one of the most common and deadly cancers worldwide. Recent evidence has demonstrated that dysregulation of long noncoding RNAs (lncRNA) is associated with different hallmarks of cancer. lncRNAs also were suggested as novel promising biomarkers for cancer diagnosis and prognosis. Despite these previous investigations, the expression pattern, diagnostic role, and hallmark association of lncRNAs in STAD remain unclear. Results In this study, The STAD lncRNA-mRNA network was constructed based on RNAs that differentially expressed among tumor and normal samples and had a strong expression correlation with others. The high degree nodes of the network were associated with overall survival. In addition, we found that the hubs' regulatory roles have previously been confirmed in different types of cancers by literature. For example, the HCG22 hub inhibited cell proliferation and invasion and induced apoptosis in oral squamous cell carcinoma (OSCC) cells. The levels of PCNA, Vimentin, and Bcl2 were decreased and E-cadherin and Bax expression was elevated in OSCC cells after HCG22 overexpression. Additionally, HCG22 overexpression inhibited the Akt, mTOR, and Wnt/beta-catenin pathways. Then lncRNAs were mapped to their related GO terms and cancer hallmarks. Based on these mappings, we predict the hallmarks that might be associated with each lncRNA. Finally, the literature review confirmed our prediction. Among the 20 lncRNAs of the STAD network, 11 lncRNAs (LINC02560, SOX21-AS1, C5orf66-AS1, HCG22, PGM5-AS1, NALT1, ENSG00000241224.2, TINCR, MIR205HG, HNF4A-AS1, ENSG00000262756) demonstrated expression correlation with overall survival (OS). Based on expression analysis, survival analysis, hallmark associations, and literature review, LINC02560, SOX21-AS1, C5orf66-AS1, HCG22, PGM5-AS1, NALT1, ENSG00000241224.2, TINCR, MIR205HG, HNF4A-AS1 plays a regulatory role in STAD. For example, our prediction of association between C5orf66-AS1 expression dysregulation and sustaining proliferative signal and Activating invasion and metastasis has been confirmed in STAD, OSCC and cervical cancer. Finally, we developed a lncRNA signature with SOX21-AS1 and LINC02560, which classified patients into high and low-risk subgroups with significantly different survival outcomes. The mortality rate of the high-risk patients was significantly higher compared to the low-risk patients (28/1% vs 60.13). Conclusion These findings help in designing more precise and detailed experimental studies to find STAD biomarkers and therapeutic targets.

Automated summary

This study constructed a STAD lncRNA-mRNA network and found that the high degree nodes were associated with overall survival and had been confirmed in other cancers. Through mapping lncRNAs to GO terms and cancer hallmarks, the potential associations between lncRNAs and hallmarks were predicted and confirmed through literature review. Furthermore, a lncRNA signature was developed to classify STAD patients into high and low-risk subgroups with significantly different survival outcomes.