上皮细胞粘附分子（EpCAM）已知在许多癌症类型中高度表达并促进癌症进展，包括结直肠癌。转移是癌症治疗失败的主要原因之一，EpCAM信号在转移过程中的参与尚不清楚。我们提出了EpCAM信号与HGFR信号的潜在相互作用，以控制结直肠癌的转移活性。我们进行了免疫共沉淀（IP）、酶联免疫吸附测定（ELISA）和荧光共振能量转移（FRET）实验，以探索EpCAM的细胞外结构域（EpEX）与HGFR的相互作用。我们通过免疫印迹法确定了结直肠癌细胞系中蛋白质的表达水平。通过增殖、迁移和侵袭分析，研究了EpEX在结直肠癌中的功能。通过尾静脉注射法验证了联合治疗在转移和原位结直肠癌模型中的有效性。本研究表明，EpEX与HGFR结合并诱导结肠癌细胞下游信号传导。此外，EpEX和HGF共同介导HGFR信号传导。此外，EpEX通过激活ERK和FAK-AKT信号通路，增强结肠癌细胞的上皮-间充质转化和转移潜力，并通过降低GSK3β的活性进一步稳定活性的β-catenin和Snail蛋白。最后，我们展示了抗EpCAM中和抗体（EpAb2-6）和HGFR抑制剂（crizotinib）的联合治疗显著抑制了结直肠癌转移和原位动物模型中的肿瘤进展，并延长了生存时间。我们的发现揭示了EpCAM信号促进结直肠癌转移的分子机制，进一步表明EpAb2-6和crizotinib的联合治疗可能是治疗高EpCAM表达癌症患者的有效策略。 © 2023. BioMed Central Ltd., part of Springer Nature.

Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer.Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models.This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer.Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression.© 2023. BioMed Central Ltd., part of Springer Nature.