Yun Li1, Chenying Liu2, Xin Zhang3, Xiaodi Huang4, Shujun Liang2, Feiyue Xing5, Han Tian6. 1. Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, 510632, China. yunli@jnu.edu.cn. 2. Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. 3. Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China. 4. Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, 510632, China. 5. Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, 510632, China. tfyxing@jnu.edu.cn. 6. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. tianhan@mail2.sysu.edu.cn.
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.
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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Authors: Maartje G Noordhuis; Rudolf S N Fehrmann; G Bea A Wisman; Esther R Nijhuis; Jelmer J van Zanden; Perry D Moerland; Emiel Ver Loren van Themaat; Haukeline H Volders; Mirjam Kok; Klaske A ten Hoor; Harry Hollema; Elisabeth G E de Vries; Geertruida H de Bock; Ate G J van der Zee; Ed Schuuring Journal: Clin Cancer Res Date: 2011-03-08 Impact factor: 12.531