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Soluble E-cadherin: a critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling

Oncogene volume 33, pages 225–235 (2014)Cite this article

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Abstract

E-cadherin, a cell–cell adhesion glycoprotein, is frequently downregulated with tumorigenic progression. The extracellular domain of E-cadherin is cleaved by proteases to generate a soluble ectodomain fragment, termed sEcad, which is elevated in the urine or serum of cancer patients. In this study, we explored the functional role of sEcad in the progression of skin squamous cell carcinomas (SCCs). We found that full-length E-cadherin expression was decreased and sEcad increased in human clinical tumor samples as well as in ultraviolet (UV)-induced SCCs in mice. Interestingly, sEcad associated with members of the human epidermal growth factor receptor (HER) and insulin-like growth factor-1 (IGF-1R) family of receptors in human and UV-induced mouse tumors. Moreover, in both E-cadherin-positive (E-cadherin+) and -negative (E-cadherin−) cells in vitro, sEcad activated downstream mitogen-activated protein (MAP) kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling and enhanced tumor growth, motility and invasion, the latter via activation of matrix metalloproteinase-2 (MMP-2) and MMP-9. To this end, HER, PI3K or MEK inhibitors suppressed sEcad’s tumorigenic effects, including proliferation, migration and invasion. Taken together, our data suggest that sEcad contributes to skin carcinogenesis via association with the HER/IGF-1R-family of receptors and subsequent activation of the MAPK and PI3K/Akt/mTOR pathways, thereby implicating sEcad as a putative therapeutic target in cutaneous SCCs.

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Acknowledgements

We thank Dr Yuspa (NCI) and Dr Klein-Szanto (Fox Chase Cancer Center) for the PAM212 and CC4A cells, respectively. This work was supported by NIH grants K08CA133910 (NCI) and R21ES015832 (NIEHS) to SMB as well as NIH grant R01CA138998 (NCI) to MA.

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Authors and Affiliations

  1. Department of Emergency Medicine, Health Sciences Center, Stony Brook University, Stony Brook, NY, USA

    S M Brouxhon, S Kyrkanides, X Teng, S Ghazizadeh, M Simon & L Ma

  2. Department of Dermatology, The University of Alabama at Birmingham, Birmingham, AL, USA

    M Athar

  3. Departments of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    M K O'Banion

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  1. S M Brouxhon
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Correspondence to S M Brouxhon.

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Brouxhon, S., Kyrkanides, S., Teng, X. et al. Soluble E-cadherin: a critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling. Oncogene 33, 225–235 (2014). https://doi.org/10.1038/onc.2012.563

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