上皮细胞黏附分子 (EpCAM) 调节 HGFR 信号通路以促进结肠癌的进展和转移。
Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis.
机构信息
Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan.
Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, 11529, Taiwan.
出版信息
J Transl Med. 2023 Aug 5;21(1):530. doi: 10.1186/s12967-023-04390-2.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
上皮细胞黏附分子（EpCAM）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。虽然转移是癌症治疗失败的主要原因之一，但 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 信号之间的潜在串扰，以控制结直肠癌的转移活性。
方法
通过免疫沉淀（IP）、酶联免疫吸附测定（ELISA）和荧光共振能量转移（FRET）来探索 EpCAM 的细胞外结构域（EpEX）和 HGFR 之间的相互作用。通过 Western blot 确定结直肠癌细胞系中蛋白质的表达。通过增殖、迁移和侵袭分析研究 EpEX 在结直肠癌中的功能。通过尾静脉注射方法验证联合治疗在转移和原位结肠癌模型中的作用。
结果
本研究表明，EpEX 与 HGFR 结合并在结肠癌细胞中诱导下游信号。此外，EpEX 和 HGF 共同介导 HGFR 信号。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能，并通过降低 GSK3β 活性进一步稳定活性 β-catenin 和 Snail 蛋白。最后，我们表明，抗 EpCAM 中和抗体（EpAb2-6）和 HGFR 抑制剂（crizotinib）的联合治疗可显著抑制转移性和原位动物模型中肿瘤的进展并延长生存时间。
结论
我们的研究结果阐明了 EpCAM 信号促进结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 EpCAM 高表达癌症患者的有效策略。
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