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FERMT1 mediates epithelial–mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity

Oncogene volume 36, pages 1779–1792 (2017)Cite this article

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Abstract

We previously demonstrated that fermitin family member 1 (FERMT1) was significantly overexpressed in colon cancer (CC) and associated with poor metastasis-free survival. This study aimed to investigate the precise role of FERMT1 in CC metastasis and the mechanism by which FERMT1 is involved in the epithelial–mesenchymal transition (EMT). Correlations between FERMT1 and EMT markers (E-cadherin, Slug, N-cadherin and β-catenin) were examined via immunohistochemistry in a cohort of CC tissues and adjacent normal colon mucosae. A series of in vitro and in vivo assays were performed to elucidate the function of FERMT1 in CC metastasis and underlying mechanisms. The upregulated expression of FERMT1 in CC tissues correlated positively with that of Slug, N-cadherin and β-catenin, but correlated inversely with E-cadherin expression. Altered FERMT1 expression led to marked changes in the proliferation, migration, invasion and EMT markers of CC cells both in vitro and in vivo. Investigations of underlying mechanisms found that FERMT1 interacted directly with β-catenin and activated the Wnt/β-catenin signaling pathway by decreasing the phosphorylation level of β-catenin, enhancing β-catenin nuclear translocation and increasing the transcriptional activity of β-catenin/TCF/LEF. Activation of the Wnt/β-catenin pathway by CHIR99021 reversed the effect of FERMT1 knockdown, whereas inhibition of the Wnt/β-catenin pathway by XAV939 impaired the effect of FERMT1 overexpression on EMT and cell motility. In conclusion, findings of this study suggest that FERMT1 activates the β-catenin transcriptional activity to promote EMT in CC metastasis.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (no. 81172328) and Medical Guidance Project of Shanghai Science and Technology Commission (114119a4600) (124119a1700). We thank Jiachen Nan for her generous help.

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Author notes

  1. C-C Liu, D-L Cai and F Sun: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    C-C Liu, B Yue, S-L Zhao, X-W Zhu, Z-H Peng & D-W Yan

  2. Department of Drug allocation center, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    D-L Cai

  3. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China

    F Sun & X-S Wu

  4. Department of Hapatobiliary Surgery, Affiliated Hospital of Qingdao University, Qingdao, China

    Z-H Wu

  5. Department of Pathology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    M Zhang

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Liu, CC., Cai, DL., Sun, F. et al. FERMT1 mediates epithelial–mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity. Oncogene 36, 1779–1792 (2017). https://doi.org/10.1038/onc.2016.339

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