Abstract 319: Isoform-specific induction of MAPK p38 in cervical cancer

Abstract

Abstract Cancer of the uterine cervix is the second most common female malignancy worldwide, with higher incidence occurring in developing countries. An expected 11,000 total new diagnosed cases in 2009 was reported by the American Cancer Society (Cancer Facts and Figures, 2009). Human papilloma virus (HPV) infection is considered the main causative agent for cervical cancer. Because of HPV infection, inflammation is persistent in cervical cancer and contributes to disease establishment and progression. Our previous studies have shown that inflammatory factors, like Cox2, tumor associated macrophages, and cytokines such as macrophage colony-stimulating factor (CSF-1) are elevated in cervical carcinomas. The receptor for CSF-1, encoded by the c-fms oncogene, was also elevated in cervical carcinomas compared normal cervical tissue. We have demonstrated that the transforming growth factor beta (TGF-beta), whose signaling is altered in cervical cancer, induced the expression of c-fms in cervical cancer cell lines via the activation of the c-fms trophoblast-specific promoter. In addition, TGF-beta induced the expression of c-fms in the macrophage cell line THP-1. The induction of c-fms by TGF-beta was diminished by the addition of the TGF-beta receptor 1 (A 83-01) and MAPK p38 (SB203580) inhibitors, implicating TGF-beta signaling and the p38 pathway in the regulation of c-fms expression. Four p38 isoforms encoded by distinct genes (p38α, β, γ and δ) have been identified, with more common expression observed for p38α and β and tissue-selective expression for p38γ and δ. Because SB203580 is a specific inhibitor for p38α and β but not p38γ or δ, inhibition of c-fms expression by this p38 antagonist implicated p38α and/or β in the regulation of c-fms. As p38 is a central signaling molecule in inflammation and regulation of leukocyte functions, both of which implicated in cervical carcinogenesis, our objective in this study was to examine the role of p38 in cervical carcinogenesis. We detected mRNA expression of all p38 isoforms in cervical cancer cell lines, human normal cervical tissue and cervical carcinoma samples. Protein expression of the p38 isoforms was confirmed in the cervical cancer cell lines HT-3, HeLa and CaSki. This suggested that the p38 isoforms may play distinct roles in cervical carcinogenesis. With the exception of p38α, which showed decreased expression in cervical carcinoma samples, p38β, γ, and δ showed increased expression in human cervical carcinomas compared to normal cervical tissue. The data suggest that elevated expression of p38β, γ, and δ in cervical carcinomas may play a role in cervical carcinogenesis. Thus, further studies are required to examine the specific roles of the p38 isoforms in cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 319.