Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cellular and Molecular Biology

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



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.


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.


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.


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.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    Article  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  Google Scholar 

  3. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.

    Article  Google Scholar 

  4. Chen W, Sun K, Zheng R, Zeng H, Zhang S, Xia C, et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res. 2018;30:1–12.

    Article  Google Scholar 

  5. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12:895–904.

    CAS  Article  Google Scholar 

  6. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.

    CAS  Article  Google Scholar 

  7. Wadhwa R, Song S, Lee JS, Yao Y, Wei Q, Ajani JA. Gastric cancer-molecular and clinical dimensions. Nat Rev Clin Oncol. 2013;10:643–55.

    CAS  Article  Google Scholar 

  8. Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T, Boumahdi S, et al. Identification of the tumour transition states occurring during EMT. Nature. 2018;556:463–8.

    CAS  Article  Google Scholar 

  9. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.

    CAS  Article  Google Scholar 

  10. Noordhuis MG, Fehrmann RS, Wisman GB, Nijhuis ER, van Zanden JJ, Moerland PD, et al. Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res. 2011;17:1317–30.

    CAS  Article  Google Scholar 

  11. Zhang Y, Wang X. Targeting the Wnt/beta-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13:165.

    Article  Google Scholar 

  12. Tian X, Liu Z, Niu B, Zhang J, Tan TK, Lee SR, et al. E-cadherin/beta-catenin complex and the epithelial barrier. J Biomed Biotechnol. 2011;2011:567305.

    PubMed  PubMed Central  Google Scholar 

  13. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  Google Scholar 

  14. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.

    CAS  Article  Google Scholar 

  15. Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, et al. Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas. Cancer Cell. 2018;33:721–35 e728.

    CAS  Article  Google Scholar 

  16. Engqvist H, Parris TZ, Kovacs A, Ronnerman EW, Sundfeldt K, Karlsson P et al. Validation of novel prognostic biomarkers for early-stage clear-cell, endometrioid and mucinous ovarian carcinomas using immunohistochemistry. Front Oncol. 2020;10:162.

  17. Gao HJ, Zheng M, Sun SJ, Wang HW, Yue ZG, Zhu Y, et al. Chaperonin containing TCP1 subunit 5 is a tumor associated antigen of non- small cell lung cancer. Oncotarget. 2017;8:64170–9.

    Article  Google Scholar 

  18. Hallal S, Russell BP, Wei H, Lee MYT, Toon CW, Sy J et al. Extracellular vesicles from neurosurgical aspirates identifies chaperonin containing TCP1 subunit 6A as a potential glioblastoma biomarker with prognostic significance. Proteomics 2019;19:e1800157.

  19. He JC, McLaughlin RP, van der Beek L, Canisius S, Wessels L, Smid M, et al. Integrative analysis of genomic amplification-dependent expression and loss-of-function screen identifies ASAP1 as a driver gene in triple-negative breast cancer progression. Oncogene. 2020;39:4118–31.

    CAS  Article  Google Scholar 

  20. Li WL, Liu J, Zhao HT. Prognostic power of a chaperonin containing TCP-1 subunit genes panel for hepatocellular carcinoma. Front. Genet. 2021;12:668871.

  21. Nibbe RK, Markowitz S, Myeroff L, Ewing R, Chance MR. Discovery and scoring of protein interaction subnetworks discriminative of late stage human colon cancer. Mol Cell Proteom. 2009;8:827–45.

    CAS  Article  Google Scholar 

  22. Akagi T, Shiraishi N, Kitano S. Lymph node metastasis of gastric cancer. Cancers (Basel). 2011;3:2141–59.

    Article  Google Scholar 

  23. Huber AH, Weis WI. The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell. 2001;105:391–402.

    CAS  Article  Google Scholar 

  24. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

    CAS  Article  Google Scholar 

  25. Nanki K, Toshimitsu K, Takano A, Fujii M, Shimokawa M, Ohta Y, et al. Divergent routes toward Wnt and R-spondin Niche independency during human gastric carcinogenesis. Cell. 2018;174:856–69.e817.

    CAS  Article  Google Scholar 

  26. Chen HN, Yuan KF, Xie N, Wang K, Huang Z, Chen Y, et al. PDLIM1 Stabilizes the E-cadherin/beta-catenin complex to prevent epithelial-mesenchymal transition and metastatic potential of colorectal cancer cells. Cancer Res. 2016;76:1122–34.

    CAS  Article  Google Scholar 

  27. Tang Y, Liu ZY, Zhao L, Clemens TL, Cao X. Smad7 stabilizes beta-catenin binding to E-cadherin complex and promotes cell-cell adhesion. J Biol Chem. 2008;283:23956–63.

    CAS  Article  Google Scholar 

  28. Liang TS, Zheng YJ, Wang J, Zhao JY, Yang DK, Liu ZS. MicroRNA-506 inhibits tumor growth and metastasis in nasopharyngeal carcinoma through the inactivation of the Wnt/beta-catenin signaling pathway by down-regulating LHX2. J Exp Clin Cancer Res. 2019;38:97.

    Article  Google Scholar 

  29. Maftouh M, Belo AI, Avan A, Funel N, Peters GJ, Giovannetti E, et al. Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/beta-catenin signalling in pancreatic adenocarcinoma. Oncotarget. 2014;5:5335–49.

    Article  Google Scholar 

  30. Wang N, Yan H, Wu D, Zhao Z, Chen X, Long Q, et al. PRMT5/Wnt4 axis promotes lymph-node metastasis and proliferation of laryngeal carcinoma. Cell Death Dis. 2020;11:864.

    Article  Google Scholar 

  31. Xu X, Zhang M, Xu F, Jiang S. Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities. Mol Cancer. 2020;19:165.

    CAS  Article  Google Scholar 

  32. Yu J, Tao S, Hu P, Wang R, Fang C, Xu Y, et al. CCR7 promote lymph node metastasis via regulating VEGF-C/D-R3 pathway in lung adenocarcinoma. J Cancer. 2017;8:2060–8.

    Article  Google Scholar 

  33. Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 2001;61:6050–4.

    CAS  PubMed  Google Scholar 

  34. Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N. Engl J Med. 2008;359:453–62.

    CAS  Article  Google Scholar 

  35. Yasuda K, Adachi Y, Shiraishi N, Inomata M, Takeuchi H, Kitano S. Prognostic effect of lymph node micrometastasis in patients with histologically node-negative gastric cancer. Ann Surg Oncol. 2002;9:771–4.

    Article  Google Scholar 

Download references


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).

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

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.

Consent to publish

All contributing authors agree to the publication of this article. All subjects have written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links