Background: The extracellular matrix modulates the hallmarks of cancer. Here we examined the role of agrin - a member of this matrix - in progression of oral squamous cell carcinoma (OSCC). Methods: We evaluated the immunohistochemical expression of agrin in OSCC and dysplasias. Benign lesions were used as control. In subsequent experiments, we investigated whether the silencing of agrin interferes with tumour expansion both in vitro as well as in vivo. To gain insights into the role of agrin, we identified its protein network (interactome) using mass spectrometry-based proteomics and bioinformatics. Finally, we evaluated the clinical relevance of agrin interactome. Results: Agrin was elevated in malignant and premalignant lesions. Further, we show that agrin silencing interferes with cancer cell motility, proliferation, invasion, colony and tumour spheroid formation, and it also reduces the phosphorylation of FAK, ERK and cyclin D1 proteins in OSCC cells. In orthotopic model, agrin silencing reduces tumour aggressiveness, like vascular and neural invasion. From a clinical perspective, agrin contextual hubs predict a poor clinical prognosis related with overall survival. Conclusions: Altogether, our results demonstrate that agrin is a histological marker for the progression of oral cancer and is a strong therapeutic target candidate for both premalignant and OSCC lesions.
Nota bibliográficaFunding Information:
CONICYT Becas-Chile Scholarship 8540/2014 (to C.R.), FONDECYT 11140507 (to W.A. G.-A.) and FAPESP Grants 2009/54067-3, 2010/19278-0 and 2016/07846-0 (to A.F.P.L.) supported this work.
Funding: CONICYT Becas-Chile Scholarship 8540/2014 (to C.R.), FONDECYT 11140507 (to W.A. G.-A.) and FAPESP Grants 2009/54067-3, 2010/19278-0 and 2016/07846-0 (to A.F.P.L.) supported this work.
© 2018 Cancer Research UK.