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Cellular and Molecular Biology

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

Abstract

Background

Lymph node (LN) metastasis confers gastric cancer (GC) progression, poor survival and cancer-related death. Aberrant activation of Wnt/β-catenin promotes epithelial-mesenchymal transition (EMT) and LN metastasis, whereas the constitutive activation mutation of Wnt/β-catenin is rare in GC, suggesting that the underlying mechanisms enhancing Wnt/β-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 β-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 β-catenin, thereby releasing β-catenin to the nucleus and enhancing Wnt/β-catenin signalling activity and EMT.

Conclusion

CCT5 promotes GC progression and LN metastasis by enhancing wnt/β-catenin activation, suggesting a great potential of CCT5 as a biomarker for GC diagnosis and therapy.

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Fig. 1: CCT5 is upregulated in GCs and correlates with LN metastasis and poor prognosis of GCs.
Fig. 2: CCT5 potently promotes GC cell survival, invasion and lymphangiogenesis in vitro.
Fig. 3: CCT5 promotes GC growth and LN metastasis in vivo.
Fig. 4: CCT5 facilitates Wnt/β-catenin signalling pathway activation and epithelial-mesenchymal transition.
Fig. 5: CCT5 interacts with E-cadherin to dissociate E-cadherin/β-catenin adhesion complex.
Fig. 6: Activation of Wnt/β-catenin signalling is crucial for CCT5-induced GC progression and LN metastasis.

Data availability

Data and materials are available upon reasonable request if applicable.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82173225, 82172927, 81802274); the Science and Technology Program of Guangzhou City (202102020022); the Natural Science Foundation of Guangdong Province (2019A1515011174); the Fundamental Research Funds for the Central Universities (19ykpy162).

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Project planning was done by HT, YL and CL. YL, CL, XH and SL performed the majority of experiments and analysed data. XZ provided the subjects, technical assistance and expertise in the clinical samples’ analysis. YL and HT wrote the manuscript. HT and FX edited the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yun Li, Feiyue Xing or Han Tian.

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The authors declare no competing interests.

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The clinical tissue specimens used in this study were obtained from and histopathologically diagnosed at Jiangmen Central Hospital. For the use of these clinical materials for research purposes, prior patients’ consents and approval from the Institutional Research Ethics Committee of Jiangmen Central Hospital were obtained. The study is compliant with all relevant ethical regulations involving human participants.

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Li, Y., Liu, C., Zhang, X. et al. CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway. Br J Cancer 126, 1684–1694 (2022). https://doi.org/10.1038/s41416-022-01747-0

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