Unveiling Novel Regulatory Mechanisms of BEX1 in Breast, Gastric, and Colorectal Cancer via a Systems Biology Approach: The Roles of lncRNAs COLCA1 and GAS6-AS1 and Their Interactions

Background : This study aimed to explore novel regulatory networks involving the BEX1 gene and its interaction with non-coding RNAs (ncRNAs) in breast cancer (BC), gastric cancer (GC), and colorectal cancer (CRC). BEX1 has been linked to tumor suppression, but its role in signaling pathways and its interactions with regulatory RNAs in these cancers has not been fully elucidated. Methods : High-throughput microarray datasets (GSE10810, GSE54129, and GSE208099) were analyzed to investigate BEX1 expression in breast cancer, gastric cancer, and colorectal cancer. The expression analysis and survival outcomes for BEX1 and selected lncRNAs were validated using the ENCORI platform. Regulatory interactions of BEX1 with proteins and microRNAs were identified using STRING and miRWalk, respectively, while lncRNA interactions were examined through lncRRIsearch. Final validation of differential expression analysis and biomarker potential was conducted using qRT-PCR, along with ROC analysis to assess diagnostic capability. Results : BEX1, identified as a tumor suppressor with low expression in breast, gastric, and colorectal cancer, demonstrated potential as a diagnostic biomarker, particularly in breast cancer (AUC: 0.8025, p = 0.0011). The lncRNAs COLCA1 and GAS6-AS1 were found to potentially regulate BEX1 expression. BEX1 exhibited significant interactions with two key proteins involved in cancer-related signaling pathways: CALML3 and LMO2. Moreover, BEX1 and these proteins demonstrated competitive interactions with miR-3616-3p, which was found to suppress BEX1 expression by targeting its 3'UTR. COLCA1 and GAS6-AS1 also exhibited dysregulated expression across breast, gastric, and colorectal cancers, suggesting their potential as diagnostic biomarkers. Conclusion : The lncRNAs GAS6-AS1 and COLCA1, alongside miR-3616-3p, may play pivotal roles in regulating cancer-related pathways, including gastric acid secretion, insulin signaling, and homeostasis. These regulatory processes occur through direct and indirect interactions between the non-coding RNAs and BEX1, further highlighting the potential of these molecules as therapeutic targets and diagnostic biomarkers.