OCIAD2-IQGAP1 interaction promotes pancreatic cancer progression by suppressing oxidative stress and mitochondria-mediated apoptosis.

[BACKGROUND] Pancreatic ductal adenocarcinoma (PDAC) ranks among the foremost causes of cancer-associated mortality globally, with a 5-year survival rate of less than 10 %. Ovarian carcinoma immunoreactive antigen domain containing 2 (OCIAD2), which has been previously implicated in ovarian carcinogenesis, has emerged as a potential oncogenic factor. However, its functional role in PDAC remains underexplored.

[METHODS] To validate the oncogenic role of OCIAD2 in PDAC, we employed a combination of multi-omics bioinformatic analyses, clinical specimen evaluations, and cellular functional assays. Further investigations were conducted to assess mitochondrial morphological dynamics, intracellular redox homeostasis, and apoptotic signaling pathways. For mechanistic exploration, we integrated transcriptomic profiling, immunoprecipitation-coupled mass spectrometry, and systematic protein-protein interaction validation assays. In vivo, both subcutaneous xenograft models and orthotopic tumor implantation models were utilized to substantiate its tumor-promoting capacities.

[RESULTS] OCIAD2 promotes tumor proliferation, migration, invasion, and resistance to gemcitabine in PDAC. It suppresses apoptosis by maintaining mitochondrial function and redox balance. These effects were associated with the activation of the PI3K/AKT pathway. Notably, OCIAD2 directly interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) via its double helical motif, and this binding further promotes PI3K/AKT pathway activation.

[CONCLUSION] OCIAD2 drives PDAC progression through binding to IQGAP1, which activates PI3K/AKT pathway; this in turn preserves mitochondrial function and suppresses apoptosis. Our study identifies OCIAD2 as a critical mediator of tumor progression and a potential therapeutic target in PDAC.