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‘MCC’ protein interacts with E-cadherin and β-catenin strengthening cell–cell adhesion of HCT116 colon cancer cells

Oncogene volume 37, pages 663–672 (2018)Cite this article

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Abstract

E-cadherin and β-catenin are key proteins that are essential in the formation of the epithelial cell layer in the colon but their regulatory pathways that are disrupted in cancer metastasis are not completely understood. Mutated in colorectal cancer (MCC) is a tumour suppressor gene that is silenced by promoter methylation in colorectal cancer and particularly in patients with increased lymph node metastasis. Here, we show that MCC methylation is found in 45% of colon and 24% of rectal cancers and is associated with proximal colon, poorly differentiated, circumferential and mucinous tumours as well as increasing T stage and larger tumour size. Knockdown of MCC in HCT116 colon cancer cells caused a reduction in E-cadherin protein level, which is a hallmark of epithelial–mesenchymal transition in cancer, and consequently diminished the E-cadherin/β-catenin complex. MCC knockdown disrupted cell–cell adhesive strength and integrity in the dispase and transepithelial electrical resistance assays, enhanced hepatocyte growth factor-induced cell scatter and increased tumour cell invasiveness in an organotypic assay. The Src/Abl inhibitor dasatinib, a candidate anti-invasive drug, abrogated the invasive properties induced by MCC deficiency. Mechanistically, we establish that MCC interacts with the E-cadherin/β-catenin complex. These data provide a significant advance in the current understanding of cell–cell adhesion in colon cancer cells.

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Acknowledgements

We thank Irvin Ng, Melissa Abas, Sabine Meessen, Monica Killen and Sean Warren for advice and technical assistance. The work was supported by Cancer Council NSW (RG 14-08, RG17-05), NHMRC (1020406, 1043501, 1089497, 1105640, 1129401), Cancer Institute NSW (10CDF232, 12CDF234), the Australian Research Council Future Fellowship (FT120100880), the Len Ainsworth Pancreatic Cancer Fellowship, Cancer Australia and Cure Cancer Australia (1049846), Gastroenterological Society of Australia, Sydney Catalyst and Tour de Cure. The contents of the published material are solely the responsibility of the administering institution, a participating institution or individual authors and do not reflect the views of the NHMRC. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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  1. F A Benthani and D Herrmann: These authors contributed equally to this work.

Authors and Affiliations

  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    F A Benthani, D Herrmann, P N Tran, L Pangon, M C Lucas, A H Allam, N Currey, S Al-Sohaily, M Giry-Laterriere, J Warusavitarne, P Timpson & M R J Kohonen-Corish

  2. St Vincent’s Clinical School, UNSW Sydney, Sydney, New South Wales, Australia

    F A Benthani, D Herrmann, P N Tran, L Pangon, P Timpson & M R J Kohonen-Corish

  3. School of Medicine, Western Sydney University, Sydney, New South Wales, Australia

    M R J Kohonen-Corish

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Benthani, F., Herrmann, D., Tran, P. et al. ‘MCC’ protein interacts with E-cadherin and β-catenin strengthening cell–cell adhesion of HCT116 colon cancer cells. Oncogene 37, 663–672 (2018). https://doi.org/10.1038/onc.2017.362

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