Investigating the Interaction of miR-۴۶۶۹ and LINC۰۰۷۰۲ with TIMP۱ in Gastric Cancer: Implications for ECM Organization

: Gastric cancer (GC) continues to be a major cause of cancer-related mortality worldwide, with its high incidence and poor prognosis largely attributed to the lack of early diagnostic biomarkers. Here we aimed to identify potential prognostic targets for GC based on bioinformatics. Method: Three gene expression datasets (GSE۱۶۱۵۳۳, GSE۱۱۸۹۱۶, and GSE۵۴۱۲۹) sourced from the Gene Expression Omnibus (GEO) database were merged and differentially expressed genes (DEGs) were identified after preprocessing using R Studio. Enrichment and pathway analyses were conducted using ENRICHR and Reactome. Hub genes were carried out by a protein-protein interaction (PPI) network constructed with STRING. mRNA survival analysis and validation were performed by GEPIA۲. miRNA interactions were analyzed using miRWalk online database while its survival analysis was performed via ENCORI. In addition, IncRNA interactions were examined using IncRRIsearch database. miRNA-mRNA and lncRNA-mRNA correlation analyses were performed using ENCORI online database. Results: A total of ۲۰۷ DEGs were screened in ۲۱۸ samples (|log۲FC|>۱.۵, adj.p.value<۰.۰۵). Based on ENRICHR and Reactome databases, Extracellular Matrix (ECM) Organization recognized as the main signaling pathway. Hub genes MMP۳, MMP۱, COL۵A۲, COL۱۰A۲ and TIMP۱ were identified using STRING, in addition TIMP۱ was validated as upregulated gene via ENCORI. miRWALK database identified hsa-miR-۴۶۶۹ as a significant miRNA interacting with TIMP۱ (interaction energy=-۲۳.۸, position: ۳’UTR). LINC۰۰۷۰۲ (interaction energy= -۳۰۷۸.۴۹) was identified as significant lncRNAs interacting with TIMP۱ using lncRRIsearch. Survival analysis indicated no significant impact on survival based on TIMP۱ and hsa-miR-۴۶۶۹ expression levels in high and low expression groups. Conclusion: In this study TIMP۱ was identified as a key hub gene involved in ECM Organization, validated by its upregulation in GEPIA۲ database. The negative correlation between hsa-miR-۴۶۶۹ and TIMP۱ suggests a potential indirect regulatory mechanism, while the positive correlation with LINC۰۰۷۰۲ support the hypothesis that this lncRNA may act as competing endogenous RNAs (ceRNAs), sequestering miRNA that target TIMP۱. The expression levels of TIMP۱ and hsa-miR-۴۶۶۹ did not significantly impact survival outcomes, although their essential roles in extracellular matrix (ECM) organization provide valuable insights into cellular dynamics. This discovery underscores the complexity of gene regulation and suggests that these molecules are part of a larger, intricate network. Further research is crucial to unravel the specific mechanisms involved and to explore their potential therapeutic benefits, offering promising directions for future advancements in ECM-related treatments.

کلیدواژه ها:

Gastric cancer ، Bioinformatics ، Gene expression analysis ، Meta-analysis ، Therapeutic biomarkers