Iqgap3 and Myc Interaction Regulates Damaged Stomach Repair and Early Gastric Carcinogenesis

The gastrointestinal tract is frequently subjected to tissue damage caused by various environmental stressors. Adult stem cells conduct tissue repair through regenerative programs with striking parallels to carcinogenesis, implying that dysregulated repair mechanisms initiate cancer development. Previously, we identified Iqgap3 as a marker of rapidly proliferating stem cells within the isthmus of gastric glands, a region essential for maintaining tissue homeostasis. Following tissue injury, we observed upregulation of Iqgap3 expression and activation of Myc signaling pathways, particularly within the fully differentiated chief cell population. Given that Myc is a major oncoprotein, our findings implicate Iqgap3 as a critical mediator in the stomach repair process and carcinogenesis. To understand how the role of Iqgap3 in tissue repair may be hijacked for carcinogenesis, we developed a conditional knockout (cKO) mouse model that attenuates Iqgap3 expression in gastric epithelial cells. Tissue damage and Iqgap3 deletion were induced by high-dose tamoxifen (HDT) treatment. Iqgap3-cKO mice were markedly compromised in tissue repair, exhibiting reduced cellular proliferation and chief cell population even one month after tissue injury. Transcriptomic analyses revealed that Iqgap3 deficiency suppressed the Myc signaling pathway and stem cell activity in the stomach, indicating a causal link between Iqgap3 and Myc during tissue regeneration. Furthermore, Iqgap3 depletion in oncogenic KrasG12D-induced metaplasia mouse model and KrasG12D-induction with Apc-depleted dysplasia mouse model protected against formation of metaplasia and dysplasia. Mechanistically, Iqgap3 deficiency led to reduced expression of neoplastic factors, such as CD44, Aqp5 and Trop2. Interestingly, Myc phosphorylation was attenuated in Iqgap3-cKO mice. We further showed that Iqgap3 directly interacted with Myc, which reinforces a role of Iqgap3 in enhancing Myc activity. Our findings highlight the critical roles of the Iqgap3-Myc axis in the regulation of stem cell activity, gastric tissue regeneration and precancerous metaplasia and dysplasia development. These insights provide a mechanistic framework for understanding the intersection of tissue repair and early carcinogenic processes. Junichi Matsuo, Mitsuhiro Shimura, Jungwon Lee, Linda S. Chuang, Wei Peng Yong, Yoshiaki Ito. Iqgap3 and Myc interaction regulates damaged stomach repair and early gastric carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 121.