Abstract
Abstract An important feature of cervical squamous carcinogenesis is genomic instability caused by deregulated expression of HPV oncogenes in proliferating epithelial cells. A genomic imbalance that is commonly selected in advanced cervical squamous cell carcinoma (SCC) is copy number gain of chromosome 5p. One gene that is likely to drive selection of this abnormality is the oncostatin-M receptor (OSMR; located at 5p13.1), which is commonly up-regulated in cervical SCC and produces a significantly worse clinical outcome when over-expressed. Cervical SCC cells that over-expressed OSMR showed enhanced responsiveness to the major ligand OSM, which induced multiple pro-malignant effects, including increased cell migration and invasiveness. We now show that transglutaminase-2 (TGM2) is an important mediator of the ligand-dependent phenotypic effects of OSMR over-expression in cervical carcinoma cells. TGM2 expression correlated with disease progression and with OSMR levels in clinical samples of SCC of the cervix and head and neck. TGM2 depletion in cervical SCC cells abrogated the increased migration and invasiveness induced by OSM. TGM2 was shown to interact with integrin-α5β1 and fibronectin in cervical SCC cells, with OSM treatment strengthening the interaction. Importantly, integrin-α5β1 and fibronectin were over-expressed in cervical SCC samples, where levels correlated with those of OSMR. We conclude that an OSMR-TGM2-integrin-α5β1 pathway is of biological significance in cervical SCC and a candidate for therapeutic targeting. Citation Format: Maria M. Caffarel, Anasuya Chattopadhyay, Cinzia G. Scarpini, Nicholas Coleman. Transglutaminase-2 mediates the pro-malignant effects of oncostatin-M receptor overexpression in cervical squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2013-4383
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