RKIP Inhibition in Cervical Cancer Is Associated with Higher Tumor Aggressive Behavior and Resistance to Cisplatin Therapy
Open Access
- 19 March 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (3), e59104
- https://doi.org/10.1371/journal.pone.0059104
Abstract
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.Keywords
This publication has 61 references indexed in Scilit:
- HPV16 Oncoproteins Induce MMPs/RECK-TIMP-2 Imbalance in Primary Keratinocytes: Possible Implications in Cervical CarcinogenesisPLOS ONE, 2012
- Downregulation of RKIP Is Associated with Poor Outcome and Malignant Progression in GliomasPLOS ONE, 2012
- A New Model for Raf Kinase Inhibitory Protein Induced Chemotherapeutic ResistancePLOS ONE, 2012
- Raf Kinase Inhibitory Protein Protects Cells against Locostatin-Mediated Inhibition of MigrationPLOS ONE, 2009
- Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7The EMBO Journal, 2009
- Identification of RKIP as an Invasion Suppressor Protein in Nasopharyngeal Carcinoma by Proteomic AnalysisJournal of Proteome Research, 2008
- Loss of Raf Kinase Inhibitory Protein Induces Radioresistance in Prostate CancerInternational Journal of Radiation Oncology*Biology*Physics, 2008
- Loss of Raf Kinase Inhibitor Protein Promotes Cell Proliferation and Migration of Human Hepatoma CellsGastroenterology, 2006
- Raf Kinase Inhibitory Protein Regulates Aurora B Kinase and the Spindle CheckpointMolecular Cell, 2006
- Papillomaviruses and cancer: from basic studies to clinical applicationNature Reviews Cancer, 2002