Cytosolic Cadherin 4 promotes angiogenesis and metastasis in papillary thyroid cancer by suppressing the ubiquitination/degradation of ß-catenin.

ABSTRACT

BACKGROUND: Although the long-term prognosis of papillary thyroid cancer (PTC) is favorable, distant metastasis significantly compromises the prognosis and quality of life for patients with PTC. The Cadherin family plays a pivotal role in tumor metastasis; however, the involvement of Cadherin 4 (CDH4) in the metastatic cascade remains elusive. METHODS: The expression and subcellular localization of CDH4 were determined through immunohistochemistry, immunofluorescence, and western blot analyses. The impact of CDH4 on cell migration, invasion, angiogenesis, and metastasis was assessed using transwell assays, tube formation assays, and animal experiments. Immunoprecipitation assay and mass spectrometry were employed to examine protein associations. The influence of CDH4 on the subcellular expression of ß-catenin and active ß-catenin was investigated via western blotting and immunofluorescence. Protein stability and ubiquitination assay were employed to verify the impact of CDH4 on ß-catenin degradation. Rescue experiments were performed to ensure the significance of CDH4 in regulating nuclear ß-catenin signaling. RESULTS: CDH4 was found to be significantly overexpressed in PTC tissues and predominantly localized in the cytoplasm. Furthermore, the overexpression of CDH4 in tumor tissues is associated with lymph node metastasis in PTC patients. Cytosolic CDH4 promoted the migration, invasion, and lung metastasis of PTC cells and stimulated the angiogenesis and tumorigenesis of PTC; however, this effect could be reversed by Tegavivint, an antagonist of ß-catenin. Mechanistically, cytosolic CDH4 disrupted the interaction between ß-catenin and ß-TrCP1, consequently impeding the ubiquitination process of ß-catenin and activating the nuclear ß-catenin signaling. CONCLUSIONS: CDH4 induces PTC angiogenesis and metastasis via the inhibition of ß-TrCP1-dependent ubiquitination of ß-Catenin.