Abstract
Cervical cancer is one of the leading causes of cancer death in women worldwide. Persistent infection with high-risk human papillomavirus (HPV) types is the main risk factor for the development of cervical cancer precursor lesions. HPV persistence and tumor development is usually characterized by innate immune system evasion. Alterations in Toll-like receptors (TLR) expression and activation may be important for the control of HPV infections and could play a role in the progression of lesions and tumors. In the present study, we analyzed the mRNA expression of 84 genes involved in TLR signaling pathways. We observed that 80% of the differentially expressed genes were downregulated in cervical cancer cell lines relative to normal keratinocytes. Major alterations were detected in genes coding for several proteins of the TLR signaling axis, including TLR adaptor molecules and genes associated with MAPK pathway, NFκB activation and antiviral immune response. In particular, we observed major alterations in the HMGB1-TLR4 signaling axis. Functional analysis also showed that HMGB1 expression is important for the proliferative and tumorigenic potential of cervical cancer cell lines. Taken together, these data indicate that alterations in TLR signaling pathways may play a role in the oncogenic potential of cells expressing HPV oncogenes.
Highlights
Cervical cancer is one of the leading causes of cancer death in women worldwide
A positive correlation has been detected between the expression of TLR4, TLR7, and TLR9 and the development and progression of cervical intraepithelial neoplasia (CIN) and cervical carcinoma associated with HPV169
To determine the overall effect of human papillomavirus (HPV) on the Toll-like receptors (TLR) pathway, we analyzed the mRNA expression of 84 genes involved in TLR signaling in normal primary human keratinocytes (PHK) and the cervical cancer cell lines C33A, HeLa, and SiHa using a commercial quantitative PCR array
Summary
Cervical cancer is one of the leading causes of cancer death in women worldwide. Persistent infection with high-risk human papillomavirus (HPV) types is the main risk factor for the development of cervical cancer precursor lesions. Two HPV oncoproteins, E6 and E7, are the only viral products constitutively expressed in cervical tumors and are required for the maintenance of the transformed phenotype[2] These proteins are responsible for alterations in several signaling pathways of the host cell, including those involved in regulating cell differentiation, proliferation, and apoptosis[3]. TLR are a family of membrane proteins that actively participate in this process These receptors bind to molecular patterns such as lipopolysaccharide (LPS), double-stranded RNA (dsRNA), and flagellin from many pathogens including bacteria, fungi, and viruses, as well as, molecular patterns coming from danger signals produced by cells on distress. A positive correlation has been detected between the expression of TLR4, TLR7, and TLR9 and the development and progression of CIN and cervical carcinoma associated with HPV169
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