Abstract 3443: Bipotential role of retinoblastoma binding protein 9 in sporadic colorectal cancer and colitis-associated cancer

Abstract Retinoblastoma-binding protein 9 (RBBP9) is expressed in various human cancers and has been identified as a serine hydrolase promoting cancer progression by antagonizing TGFβ signaling. While its roles in pancreatic cancer have been explored, little is known about its function in intestinal tumorigenesis. Using human samples and mouse models, we investigated the bipotential role of RBBP9 in sporadic colorectal cancer (CRC) and colitis-associated cancer (CAC).Human surgical samples revealed that RBBP9 expression is significantly lower in CAC compared to sporadic CRC. Sporadic CRC is driven by Wnt/β-catenin activation, whereas CAC involves inflammation-associated pathways such as mTORC1 and IL6/JAK/STAT3 signaling. Consistent with these findings, Rbbp9-/- mice exhibited increased colitis severity and enhanced CAC tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model. Transcriptomic analysis of AOM/DSS-treated tumors revealed upregulation of inflammatory and proliferation-associated pathways, such as mTORC1 and IL6/JAK/STAT3, while Wnt/β-catenin and mitotic signatures were downregulated, indicating inflammation-driven tumorigenesis independent of Wnt signaling in CAC.In the ApcMin/+ model of spontaneous intestinal tumorigenesis, RBBP9 loss led to fewer and smaller tumors in the small intestine, accompanied by reduced proliferative activity and downregulation of cell cycle-related pathways (e.g., Myc targets and G2M checkpoint). Interestingly, tumors from ApcMin/+;Rbbp9-/- mice exhibited enrichment of inflammatory and interferon-related signatures, including “oxidative phosphorylation” and “interferon alpha/gamma response, ” though these changes did not lead to increased tumor proliferation without inflammatory stimuli. However, when ApcMin/+;Rbbp9-/- mice were treated with DSS, a significant increase in inflammation-mediated tumorigenesis was observed in the colon, accompanied by elevated Ki67 and pS6 staining, markers of proliferative activity.Collectively, these findings highlight the bipotential role of RBBP9 in intestinal tumorigenesis. In human CAC, reduced RBBP9 expression correlates with inflammation-driven pathways, while in sporadic CRC, higher RBBP9 expression supports tumor progression via Wnt/β-catenin and cell cycle pathways. These results demonstrate that RBBP9 functions as a context-dependent regulator, suppressing inflammation-mediated tumorigenesis while supporting spontaneous tumorigenesis through proliferative pathways. Targeting RBBP9 may offer novel therapeutic strategies tailored to distinct CRC subtypes, depending on their inflammatory or non-inflammatory origins. Citation Format: Yuki Nakanishi, Kensuke Hamadaa, Yu Muta, Mayuki Omatsu, Kosuke Iwane, Munehiro Ikeda, Jiayu Chen, Yoko Masui, Naoki Aoyama, Hiroki Kitamoto, Nobuyuki Agatsuma, Go Yamakawa, Takahiro Utsumi, Makoto Okabe, Shuji Yamamoto, Akihisa Fukuda, Hiroshi Seno. Bipotential role of retinoblastoma binding protein 9 in sporadic colorectal cancer and colitis-associated cancer [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 3443.