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.
Highlights
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide, accounting for 9% (529.800) of the total new cancer cases and 8% (275.100) of the total cancer deaths among females in 2008 [1]
Tumors of the cervix are divided into three different histological subtypes: Uterine squamous cell carcinomas (SCC) is the most frequent, followed by adenocarcinoma (AC) and adenosquamous carcinoma (ASC), which is an uncommon subtype [5]
No significant differences were observed in the expression levels of Raf kinase inhibitory protein (RKIP) between low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) (p = 0.404), and between cervicitis and squamous intraepithelial lesions (SIL) in general (p = 0.087), Table 1)
Summary
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide, accounting for 9% (529.800) of the total new cancer cases and 8% (275.100) of the total cancer deaths among females in 2008 [1]. Persistent infection with high-risk types of human papillomavirus (HPV) is a sine-qua-non condition for cervical cancer development. HPVs infect epithelial cells and cause a variety of lesions ranging from common warts to cervical neoplasia and cancer [2,3,4]. HPV infection alone is not enough for triggering cervical cancer and HPV-mediated oncogenesis requires the accumulation of additional genetic changes that occur over time following initial infection [6]. It may take several years for an in situ neoplasm to progress to an invasive carcinoma. The mechanism of clonal evolution, which involves the selection of cells with invasive or metastatic potential, remains unsolved
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