RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy

PLoS One. 2013;8(3):e59104. doi: 10.1371/journal.pone.0059104. Epub 2013 Mar 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression
  • Humans
  • MAP Kinase Signaling System
  • Middle Aged
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Phosphatidylethanolamine Binding Protein / genetics
  • Phosphatidylethanolamine Binding Protein / metabolism*
  • Treatment Outcome
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology*

Substances

  • Antineoplastic Agents
  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein

Grant support

This work was partially supported by the Portuguese Fundação para a Ciência e Tecnologia (grant PTDC/SAU-TOX/114549/2009). Olga Martinho and Sara Granja were recipients of PhD fellowships (SFRH/BD/36463/2007 and SFRH/BD/51062/2010, respectively), and Filipe Pinto and Vera Miranda-Gonçalves were recipients of research fellowships (UMINHO/BI/016/2011 and SFRH/BI/33503/2008, respectively), both from FCT, Portugal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.