Role and Mechanism of BRIP1 in Anoikis Resistance of Gastric Cancer

To assess the therapeutic relevance of <i>BRIP1</i> in gastric cancer (GC), we examine its functional role in conferring resistance to anoikis within GC cells and elucidate the oncogenic signaling pathways modulated by <i>BRIP1</i>. By integrating the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) databases with Least Absolute Shrinkage and Selection Operator (LASSO) regression, a novel risk score to stratify GC patients based on prognosis was generated, and a significantly differentially expressed gene, <i>BRIP1</i>, was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression associated with apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT) was quantified via RT-qPCR and Western blot (WB). 5-Ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assays were conducted to quantify proliferative activity. The protein level in axillary tumor tissues of nude mice was detected by immunohistochemistry (IHC). We established an eight-gene anoikis-related prognostic risk assessment model (<i>DUSP1</i>, <i>VCAN</i>, <i>P3H2</i>, <i>TXNIP</i>, <i>BRIP1</i>, <i>FGD6</i>, <i>GPX3</i>, and <i>RLN2</i>) for GC. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Among these genes, <i>BRIP1</i> showed significant differential expression between tumor and normal tissues, as well as normal gastric mucosal epithelial cells and GC cells. Mechanistically, <i>BRIP1</i> conferred anoikis resistance to GC cells by suppressing the generation of reactive oxygen species (ROS). We found that the PI3K inhibitor LY294002 counteracted <i>BRIP1</i>-driven oncogenic effects, which was evidenced by restored expression of key regulators governing apoptosis, cell cycle progression, and EMT, in addition to suppressed proliferation in GC cells. <i>BRIP1</i> is postulated to function upstream of the PI3K/Akt signaling cascade. This study establishes a risk scoring model and identifies <i>BRIP1</i> as a potential prognostic marker for GC.