Role of the protein RECK in HPV-mediated cell transformation

Abstract

Some HPV types, known as high-risk HPVs, are etiologically associated with almost all the cases of cervical cancer and mora than 50% or other genital carcinomas. High-risk HPVs express two oncoproteins, E6 e E7, that act on specific cellular factors promoting sustained cell proliferation, resistance to apoptosis, resistance to cytokines, immune evasion and numeric and structural chromosomal alterations. Besides, it was observed that alterations in components of the extracellular matrix (ECM), for instance the matrix metalloproteinases (MMPs) and some of their regulators, are among the mechanisms of carcinogenesis associated with HPV infection. MMPs are responsible for MEC remodeling and their up-regulation exerts a key role in several processes. Previous studies from our laboratory have shown that cells expressing HPV17 E7 oncoprotein exhibit increased MMP-9 expression levels and activity. Moreover, E7 expression is associated to the down-regulation of MMPs regulators TIMP-2 and RECK. The RECK (reversion inducing cysteine rich protein with kazal motifs) protein plays and essential function in tissue remodeling and tumor angiogenesis through the post-transcriptional regulation of MMP-2, MMP-9 and MMP-14 (MT1-MMP) activity. Furthermore, we showed that RECK expression is down-regulated in high-grade cervical lesions and cervical cancer samples when compared with cervicitis samples. Altogether, these data suggest that negative RECK regulation may constitute an important step in the natural history of cervical cancer. This study aims to determine the role of RECK in HPV-mediated carcinogenesis. To achieve this goal we will analyze the effect of RECK superexpression in the tumorigenic potential of cervical cnacer derived cell lines both in vitro and in vivo. Besides, we will analyze the effect of HPV proteins in the control of the transcriptional activity of RECK promoter. Our results will contribute to identify the role of RECK in HPV-associated tumors onset and progression. (AU)