THE ROLE OF RECK PROTEIN IN HUMAN PAPILLOMAVIRUS MEDIATED CARCINOGENESIS

Abstract

Persistent infection with high-risk Human Papillomavirus (HPV) types is the main risk factor for the development of cervical cancer. The HPV carcinogenic mechanisms include alterations in extracellular matrix (ECM) components, as matrix metalloproteinases (MMP) and its regulators. These proteins play a central role in many physiological processes and diseases such as homeostatic tissue remodeling and cancer. The REversion-inducing Cysteine-rich protein with Kazal motifs (RECK) plays a central role on tissue remodeling, tumor angiogenesis and can exert inhibitory effects on the transcription, synthesis, activation and activity of MMP-2, MMP-9 e MMP-14 (MT1-MMP). As previously published by our group, it has been observed a correlation between the HPV16 E7 oncoprotein expression, the up-regulation of MMP-9 and the down-regulation of its inhibitors, RECK and tissue inhibitor of metalloproteinases 2 (TIMP-2). Also, RECK expression was observed in higher levels in cervicitis samples than in CINII/III and invasive carcinoma samples indicating that RECK down-regulation may correlate with lesion grade. Therefore, we suggest that RECK down-regulation may be important in the natural history of cervical cancer. The present study aims to understand the role of RECK in HPV mediated carcinogenesis. In order to do this, we will assess the effects of RECK superexpression in the tumorigenic potential of cervical tumors derived cell lines. Thus, we will evaluate its clonogenic, anchorage-independent growth, migration and invasion potentials and its ability to generate tumors in immunodeficient mice when compared to control cells. All together, this study will help to determine if RECK could represent a new biomarker of cervical cancer progression and a potential target for therapy.