COMMD1 Inhibits Epithelial Mesenchymal Transition (EMT) and Liver Metastasis in Cervical Cancer Through Modulation of the Twist1/E-Cadherin Pathway.

Abstract

Our investigation was aimed at deciphering the potential role of copper metabolism MURR1 domain containing 1 (COMMD1) in cervical cancer tumorigenesis and metastasis, along with its underlying molecular mechanism, both in vitro and in vivo. To validate the research objectives, cervical cancer cell lines with stably overexpressed and knockdown COMMD1 were generated. In addition, an orthotopic murine model of cervical cancer with liver metastasis was constructed to elucidate the metastatic impact of COMMD1. Functional assays including CCK-8 assay, colony formation assay, scratch assay, and transwell invasion assay were conducted to evaluate the proliferation, migration, and invasion capabilities of cervical cancer cells. Western blot analysis and immunofluorescence double staining were performed to detect protein expression profiles and visualize actin cytoskeleton remodeling. Hematoxylin-eosin (H&E) staining and immunohistochemistry were utilized to characterize tumor histopathology and protein expression. Key findings revealed that COMMD1 was markedly downregulated in cervical cancer cell lines. Ectopic expression of COMMD1 potently impeded cell proliferation, colony formation, migration, and invasion of cervical cancer cells. Mechanistically, COMMD1, suppressed epithelial-mesenchymal transformation (EMT) by antagonizing the twist family bHLH transcription factor 1 (Twist1)/epithelial (E)-cadherin pathway, as evidenced by reduced expression of EMT-associated markers and restored E-cadherin membrane localization. In the orthotopic mouse model, COMMD1 overexpression significantly attenuated liver metastatic foci formation and blunted EMT progression. In conclusion, COMMD1 acts as a tumor suppressor in cervical cancer, with its antitumor effects primarily mediated by inhibiting Twist1-driven EMT and metastatic cascade.