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

• Published in: PloS one Vol. 8; no. 3; p. e59104
• Main Authors: Martinho, Olga, Pinto, Filipe, Granja, Sara, Miranda-Gonçalves, Vera, Moreira, Marise A R, Ribeiro, Luis F J, di Loreto, Celso, Rosner, Marsha R, Longatto-Filho, Adhemar, Reis, Rui Manuel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-03-2013; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aggressive behavior; Analysis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Assaying; Biology; Breast cancer; Cancer; Cancer metastasis; Cancer prevention; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Cervical cancer; Cervical carcinoma; Cervicitis; Chemoresistance; Chemotherapy; Cisplatin; Colonies; Development and progression; Disease Progression; Drug Resistance, Neoplasm - genetics; Etiology; Female; Gene Expression; Health risks; Health sciences; Hospitals; Human papillomavirus; Humans; Immunohistochemistry; Infections; Inhibition; Invasiveness; Kinases; Laboratories; Lesions; Lymphatic system; MAP Kinase Signaling System; Medical prognosis; Medical research; Medicine; Metastases; Metastasis; Middle Aged; Neoplasia; Neoplasms; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Oncology; Papillomavirus infections; Pathology; Phosphatidylethanolamine Binding Protein - genetics; Phosphatidylethanolamine Binding Protein - metabolism; Prostate; Protein expression; Proteins; Raf protein; Risk groups; Rodents; Squamous cell carcinoma; Tissues; Treatment Outcome; Tumors; Uterine cancer; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterus; Vascularization; Viability; Wound healing; Brazil; Portugal
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0059104

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.