Comprehensive Analysis of the Bid Gene to Uncover the Role of Novel Alternative Splicing Isoforms in Colon Adenocarcinoma: A Systematic Review of Literature and Bioinformatics Analysis Publisher



Zangooie A ; Piroozkhah M ; Mazloomnejad R ; Ahmadi A ; Ghazizadeh Ahsaei H ; Alitotonchi Z ; Shahmoradi A ; Qaderi K ; Halimi A ; Eghbali Z ; Aliabadi LS ; Forouzesh F ; Nazemalhosseinimojarad E ; Salehi Z
Source: Cancer Cell International Published:2025

Abstract

Background: Colon Adenocarcinoma (COAD) is the second leading cause of cancer-related death worldwide, with a rising incidence. Apoptosis is a key contributor to cancer, serving as a prognostic and diagnostic marker. BID, as a link between extrinsic and intrinsic apoptosis pathways, may play an important role in COAD development. Materials and methods: A systematic review was conducted to assess the role of the BID gene in COAD. A systematic review was conducted using PubMed, Web of Science, and Scopus up to December 14, 2023. Two reviewers screened articles according to the PRISMA 2020 guidelines, and the risk of bias was assessed using the ROBINS-I tool. The study protocol was registered in PROSPERO (CRD42023455350). A pan-cancer analysis of BID was performed using TCGA and HPA data. In COAD, BID expression, methylation, isoforms, and correlations with immune cell infiltration were analyzed in conjunction with clinical data. miRNAs regulating BID were investigated, and gene set enrichment analysis identified associated GO terms and KEGG pathways. Phylogenetic analysis of BID isoforms and variants was conducted using sequences from GenBank and Ensembl, aligned with Clustal Omega and NCBI tools to assess conservation and similarity. Results: From 661 articles identified across PubMed, Web of Science, and Scopus, 205 studies were included in the review, of which 17 human studies analyzed BID in COAD. BID mediates apoptosis in COAD through the Fas/FasL and Apo2/TRAIL pathways, activating DR4 and DR5, which leads to the recruitment of FADD and the activation of CASP-8 and CASP-10. CASP-8 cleaves BID into tBID, which activates BAX and BAK, causing mitochondrial outer membrane permeabilization, cytochrome c release, apoptosome formation, CASP-9 activation, and apoptosis. Apoptosis is modulated by ER stress/UPR, DPP3/CDK1, PIDD/CASP-2, NF-κB/Nur77, APPL/DCC, PI3K/AKT, HIF-1, and miR-20, MCL-1, BCL-2/BCL-xL. In COAD, BID is overexpressed, particularly in isoforms BID-L, BID-EL, and BID-S, whereas BID-Si6 remains unchanged. BID expression is lower in patients with advanced-stage and N2 disease, suggesting potential prognostic value. BID expression inversely correlates with the infiltration of B cells, CD4+ T cells, and regulatory T cells. The hsa-miR-194-3p and hsa-miR-149-5p were found to be correlated with BID expression in COAD. Phylogenetic analysis reveals that BID is evolutionarily conserved, underscoring its functional importance. Conclusions: BID, specifically the BID-EL isoform, serves as a prognostic and diagnostic biomarker in COAD, highlighting the need for further research on its potential as a therapeutic target in this disease. © The Author(s) 2025.