Kim Jeeho, Jeon Young Jin, Chang In-Youb, Lee Jung-Hee, You Ho Jin
Laboratory of Genomic Instability and Cancer Therapeutics, Gwangju, South Korea.
Department of Pharmacology, Gwangju, South Korea.
Exp Mol Med. 2025 Feb;57(1):151-166. doi: 10.1038/s12276-024-01381-1. Epub 2025 Jan 1.
Wnt signaling is essential for cell growth and tumor formation and is abnormally activated in colorectal cancer (CRC), contributing to tumor progression; however, the specific role and regulatory mechanisms involved in tumor development remain unclear. Here, we show that Ephexin1, a guanine nucleotide exchange factor, is significantly overexpressed in CRC and is correlated with increased Wnt/β-catenin pathway activity. Through comprehensive analysis, including RNA sequencing data from TCGA and functional assays, we observed that Ephexin1 promotes tumor proliferation and migration by activating the Wnt/β-catenin pathway. This effect was mediated by the interaction of Ephexin1 with Axin1, a critical component of the β-catenin destruction complex, which in turn enhanced the stability and activity of β-catenin in signaling pathways critical for tumor development. Importantly, our findings also suggest that targeting Ephexin1 may increase the efficacy of Wnt/β-catenin pathway inhibitors in CRC treatment. These findings highlight the potential of targeting Ephexin1 as a strategy for developing effective treatments for CRC, suggesting a novel and promising approach to therapy aimed at inhibiting cancer progression.
Wnt信号通路对细胞生长和肿瘤形成至关重要，在结直肠癌（CRC）中异常激活，促进肿瘤进展；然而，其在肿瘤发展中所涉及的具体作用和调控机制仍不清楚。在此，我们表明鸟嘌呤核苷酸交换因子Ephexin1在CRC中显著过表达，且与Wnt/β-连环蛋白通路活性增加相关。通过综合分析，包括来自TCGA的RNA测序数据和功能试验，我们观察到Ephexin1通过激活Wnt/β-连环蛋白通路促进肿瘤增殖和迁移。这种效应是由Ephexin1与Axin1（β-连环蛋白破坏复合物的关键成分）的相互作用介导的，这反过来又增强了β-连环蛋白在对肿瘤发展至关重要的信号通路中的稳定性和活性。重要的是，我们的研究结果还表明，靶向Ephexin1可能会提高Wnt/β-连环蛋白通路抑制剂在CRC治疗中的疗效。这些发现突出了靶向Ephexin1作为开发CRC有效治疗策略的潜力，为旨在抑制癌症进展的治疗提出了一种新颖且有前景的方法。
