Abstract 5125: Low-density lipoprotein receptor-related protein 1 as a negative regulator in epithelial-mesenchymal transition and metastasis of colorectal cancer: Targeting the Wnt/β-Catenin signaling pathway

Abstract Background and aim: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in various cellular processes, including cancer progression. Its role and the underlying mechanisms in the metastasis of colorectal cancer (CRC) remain to be fully elucidated. Methods: LRP1 expression in CRC was assessed by immunohistochemistry in a cohort of 400 tissue samples, with subsequent Kaplan-Meier survival analysis. In vitro studies included real-time PCR, western blot, colony formation assays, immunofluorescence assays, wound healing assays, and migration and invasion experiments to explore LRP1's impact on epithelial-mesenchymal transition (EMT), cell migration, and invasion. In vivo, mouse xenograft and metastasis models were employed to assess tumorigenicity and metastatic potential, with immunohistochemistry, real-time PCR, and western blot used to evaluate protein expression levels. Luciferase reporter assays were conducted to investigate LRP1's influence on the Wnt/β-catenin signaling pathway. Results: LRP1 was found to be highly expressed in 68.2% of the CRC specimens and was significantly associated with membranous E-cadherin expression and cytoplasmic β-catenin localization. Elevated LRP1 levels, in conjunction with reduced Wnt/β-catenin signaling activity, correlated with decreased nuclear accumulation of β-catenin and predicted better prognosis. LRP1 suppressed cell proliferation, migration, and invasion both in vitro and in vivo, and hindered the nuclear translocation of β-catenin. Wnt/β-catenin signaling could counteract LRP1's effects on EMT and enhance the expression of vimentin, a mesenchymal marker. Restoring vimentin expression mimicked the effects of LRP1 knockdown without altering Wnt/β-catenin activity. Conclusions: LRP1 appears to be a significant negative regulator in the EMT, invasion, and metastasis of CRC, potentially acting upstream of the Wnt/β-catenin signaling pathway. Therefore, the combined targeting of LRP1 and the Wnt/β-catenin pathway may offer a novel and promising therapeutic strategy for CRC patients. Citation Format: Zhihong Zhang, Dingwen Zhong, Tanxing Cai, Ze Li, Yufeng Chen, Xiaojian Wu, Xiaobin Zheng. Low-density lipoprotein receptor-related protein 1 as a negative regulator in epithelial-mesenchymal transition and metastasis of colorectal cancer: Targeting the Wnt/β-Catenin signaling pathway [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 5125.