CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway

Background Lymph node (LN) metastasis confers gastric cancer (GC) progression, poor survival and cancer-related death. Aberrant activation of Wnt/beta-catenin promotes epithelial-mesenchymal transition (EMT) and LN metastasis, whereas the constitutive activation mutation of Wnt/beta-catenin is rare in GC, suggesting that the underlying mechanisms enhancing Wnt/beta-catenin activation need to be further investigated and understood. Methods Bioinformatics analyses and immunohistochemistry (IHC) were used to identify and detect LN metastasis-related genes in GC. Cellular functional assays and footpad inoculation mouse model illustrate the biological function of CCT5. Co-immunoprecipitation assays, western blot and qPCR elucidate the interaction between CCT5 and E-cadherin, and the regulation on beta-catenin activity. Results CCT5 is upregulated in LN metastatic GCs and correlates with poor prognosis. In vitro assays prove that CCT5 markedly promotes GC cell proliferation, anti-anoikis, invasion and lymphatic tube formation. Moreover, CCT5 enhances xenograft GC growth and popliteal lymph node metastasis in vivo. Furthermore, CCT5 binds the cytoplasmic domain of E-cadherin and abrogates the interaction between E-cadherin and beta-catenin, thereby releasing beta-catenin to the nucleus and enhancing Wnt/beta-catenin signalling activity and EMT. Conclusion CCT5 promotes GC progression and LN metastasis by enhancing wnt/beta-catenin activation, suggesting a great potential of CCT5 as a biomarker for GC diagnosis and therapy.