Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil.
Centre of Translational Oncology, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil.
Sci Rep. 2018 Feb 22;8(1):3476. doi: 10.1038/s41598-018-21416-8.
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.
宫颈癌是全球女性癌症死亡的主要原因之一。持续性感染高危型人乳头瘤病毒（HPV）是宫颈癌前病变发展的主要危险因素。HPV 的持续存在和肿瘤的发展通常以先天免疫系统逃避为特征。 Toll 样受体（TLR）表达和激活的改变对于控制 HPV 感染可能很重要，并可能在病变和肿瘤的进展中发挥作用。在本研究中，我们分析了 84 个参与 TLR 信号通路的基因的 mRNA 表达。我们观察到，与正常角质形成细胞相比，80%的差异表达基因在宫颈癌细胞系中下调。在 TLR 信号轴的几个蛋白编码基因中检测到主要改变，包括 TLR 衔接分子和与 MAPK 途径、NFκB 激活和抗病毒免疫反应相关的基因。特别是，我们观察到 HMGB1-TLR4 信号轴的主要改变。功能分析还表明，HMGB1 表达对于表达 HPV 致癌基因的宫颈癌细胞系的增殖和致瘤潜能很重要。综上所述，这些数据表明 TLR 信号通路的改变可能在表达 HPV 致癌基因的细胞的致癌潜能中起作用。
