RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy
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2013
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Cervical cancer is one of the most common cancers in women worldwide, being high-risk group the HPV infected, the
leading etiological factor. The raf kinase inhibitory protein (RKIP) has been associated with tumor progression and
metastasis in several human neoplasms, however its role on cervical cancer is unclear. In the present study, 259 uterine
cervix tissues, including cervicitis, cervical intraepithelial lesions and carcinomas, were analyzed for RKIP expression by
immunohistochemistry. We found that RKIP expression was significantly decreased during malignant progression, being
highly expressed in non-neoplastic tissues (54% of the samples; 73/135), and expressed at low levels in the cervix invasive
carcinomas (,15% (19/124). Following in vitro downregulation of RKIP, we observed a viability and proliferative advantage
of RKIP-inhibited cells over time, which was associated with an altered cell cycle distribution and higher colony number in a
colony formation assay. An in vitro wound healing assay showed that RKIP abrogation is associated with increased
migratory capability. RKIP downregulation was also associated with an increased vascularization of the tumors in vivo using
a CAM assay. Furthermore, RKIP inhibition induced cervical cancer cells apoptotic resistance to cisplatin treatment. In
conclusion, we described that RKIP protein is significantly depleted during the malignant progression of cervical tumors.
Despite the lack of association with patient clinical outcome, we demonstrate, in vitro and in vivo, that loss of RKIP
expression can be one of the factors that are behind the aggressiveness, malignant progression and chemotherapy
resistance of cervical cancer.
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MARTINHO, Olga et al. RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy. Plos One, California, v. 8, n. 3, p. e59104, 2013.