Abstract 6847: IGF2BP3 promotes esophageal squamous cell carcinoma progressions via Wnt/CTNNB1 pathway

Abstract

Abstract The M6A RNA modification plays a crucial role in the progression of tumors. Simultaneously, IGF2BP3 is primarily expressed in the tumor cells of squamous cell carcinoma, rather than in stromal cells, including esophageal squamous cell carcinoma (ESCC), a subtype mainly prevalent in East Asia. However, the mechanism of IGF2BP3 in the progression of esophageal squamous cell carcinoma and its role in the tumor microenvironment (TME) remain unknown and require further exploration. Our research reveals that IGF2BP3 not only plays a significant oncogenic role in tumor cells, including the activation of the Wnt pathway, PI3K-AKT pathway, and MAPK pathway, but also, the high expression of IGF2BP3 is positively correlated with the enrichment of M2 macrophages in ESCC tissues, in the TME, IGF2BP3 promotes the infiltration of M2 macrophages, ultimately facilitating the progression of ESCC. Mechanistically, IGF2BP3 enhances the translation of USP36 mRNA by directly binding to its mRNA, rather than increasing the stability of mRNA. The IGF2BP3-mediated USP36 protein elevation enhances the binding capacity with CTNNB1 protein, reducing its degradation through the ubiquitin-proteasome pathway, and following improved the Wnt/CTNNB1 pathway activating, Ultimate, IGF2BP3 aggravated the malignancy of the tumor. Additionally, the activation of the Wnt pathway promotes TGFB1 transcription and secretion, subsequently activating the polarization of M2 macrophages, infuriating the formation of the tumor immune-suppressive microenvironment, ultimately promoting the progression of esophageal squamous cell carcinoma. Our findings strongly emphasize the oncogenic role of IGF2BP3 in the progression of ESCC both in vitro and in vivo, providing new insights and perspectives for the treatment of esophageal squamous cell carcinoma. Citation Format: Zhongxian Tian, Yongjia Zhou, Yi Ding, Zhengwen Wu, Xiaogang Zhao. IGF2BP3 promotes esophageal squamous cell carcinoma progressions via Wnt/CTNNB1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6847.