IQGAP3 Overexpression Confers Survival Advantage in Biliary Tract Cancer by Stabilizing Epithelial Identity

AbstractBackground:Biliary tract cancer (BTC) is an aggressive malignancy with limited prognostic biomarkers. IQ motif containing GTPase activating protein 3 (IQGAP3) has been implicated in cell-cycle control and epithelial-mesenchymal transition (EMT) across several cancers, although its significance in BTC remains unclear.Methods:We retrospectively analyzed 131 patients who underwent curative resection for intrahepatic, perihilar, or distal cholangiocarcinoma or ampullary carcinoma at a single institution during 2016-2020. IQGAP3 expression was assessed by immunohistochemistry and quantified by QuPath-based H-scores, and associations with clinicopathological variables and survival outcomes were evaluated using Kaplan-Meier and Cox regression analyses. Functional validation was performed in HuCCT1 and TFK-1 cells via shRNA-mediated IQGAP3 knockdown, followed by RNA sequencing and gene set enrichment analysis to identify differentially enriched pathways.Results:High IQGAP3 expression was significantly associated with prolonged overall survival compared with low expression (median 97.6 vs. 64.7 months; hazard ratio 0.50, 95 percent confidence interval 0.30-0.81; P=0.005), particularly in extrahepatic cholangiocarcinoma. IQGAP3 silencing activated EMT-related transcriptional programs in both cell lines (normalized enrichment score -1.42 and -1.43; P<0.01).Conclusions:IQGAP3 overexpression in BTC stabilizes epithelial identity by attenuating EMT signaling and predicts favorable prognosis. IQGAP3 is a potential prognostic biomarker and context-dependent therapeutic target in BTC.