The role of TLRs in cervical cancer with HPV infection: a review

Abstract

The main cause of cervical cancer is persistent infection with high-risk human papilloma virus (HR-HPV), but not all human papilloma virus (HPV) infections lead to cervical cancer. The key factors that determine the outcome of HPV infection remain poorly understood, and how the host immune system protects against HPV infection is unclear. Toll-like receptors (TLRs) are a group of pattern recognition receptors present in the cytoplasm and cell membrane, and can specifically recognize pathogen-associated molecular patterns. As the key molecules of innate and acquired immunity, TLRs not only play important roles in the immune defense against infectious diseases, but also are involved in the occurrence and development of a variety of malignant tumors. In cervical cancer caused by HR-HPV infection, TLRs have been found to regulate the local immune microenvironment. The role of TLRs in HR-HPV infection and HPV-induced cervical cancer and its relationship with HPV vaccine are reviewed in this article.

Figure 1

The possible mechanism of TLR4 being correlated with cervical cancer. The combination of TLR4 and its ligand (LPS) can trigger lipid rafts flowing which results in the change of lipid raft space conformation. This conformational change provides a condition for the aggregation of NADPH oxidase subunits on lipid rafts, which activates the redox reaction of lipid rafts to produce ROS and inhibits the degradation of HIF-1α, leading to the high expression of HIF-1α.

Figure 2

Toll-like receptor signaling. The MyD88-dependent pathway results in nuclear translocation of NF-κB and induction of pro-inflammatory cytokines. TLR3 and TLR4 activate IRF-3 and induce IFN-stimulated regulatory elements through a MyD88-independent signaling pathway.

Figure 3

TLRs and T helper cell responses. PAMPs from invading pathogens bind with TLRs expressed in DCs, and DCs become activated and mature to active naive T cells. Naive T cells are primed toward specific T helper profiles: Th1, Th2, which can produce cytokines and in turn establish resistance to external pathogen invasion.

Figure 4

Synthesis of NO via TLR signaling. The TLRs are expressed on the cell surface or inside cells. TLRs use MyD-88 for downstream signaling, but TLR3 uses TRIF protein as an adaptor molecule. In downstream signaling, the activation of NF-κB or AP-1 can upregulate gene transcription for iNOS in the nucleus, and generate highly reactive NO, which can induce some effects and promote the proliferation of tumor.

Figure 5

HPVs infect host epithelial cells through TLRs. The HPVs DNA viral replication is synchronous with host cellular DNA replication. The cells express E6/E7/E5 oncoproteins to damage the infected cells by inhibiting the expression of tumor suppressors p53 and Rb and decreasing apoptosis. E6/E7/E5 oncoproteins can also activate the PI3K/Akt/mTOR signaling pathway. All these processes enhance cell proliferation and promote tumor growth.