The effect of TLR4 on the growth and local inflammatory microenvironment of HPV-related cervical cancer in vivo

Abstract

Background: Cervical cancer is the most common malignancy of the female lower genital tract. In our previous study, we found that TLR4 promotes cervical cancer cell growth in vitro. The aim of this study was to further explore the role of TLR4 in HPV-related cervical cancer in vivo by using a nude mouse xenograft model. Methods: Cervical cancer-derived HeLa and CaSki cells (5 × 10 7 /mL) were either stimulated with an optimal concentration of LPS for the appropriate time (HeLa cells were treated with 1 μg/mL LPS for 1 h, and CaSki cells were treated with 2 μg/mL LPS for 1.5 h) or transfected with TLR4 shRNA and then injected subcutaneously into the dorsal right posterior side of nude mice. The shortest width and longest diameter of the transplanted tumors in the nude mice were measured every 3 days.TLR4, IL-6,iNOS, IL-8,COX-2, MIP-3α, TGF-β1 and VEGF expression levels in the transplanted tumor tissue were detected by immunohistochemistry. Results: The tumor formation rate was 100% in both HeLa and CaSki nude mouse groups. The tumors grew faster, and the cachexia symptoms were more serious in the LPS groups than in the control group. In contrast, the tumors grew slower, and the cachexia symptoms were milder in the TLR4-silenced groups. TLR4, iNOS, IL-6, MIP-3α and VEGF were highly expressed in the transplanted tumor tissues from the LPS groups, and their expression levels were decreased in the TLR4-silenced groups. Conclusion: TLR4 expression is closely associated with the tumorigenesis and growth of HPV-positive cervical cancer; TLR4 promotes HPV-positive cervical tumor growth and facilitates the formation of a local immunosuppressive microenvironment. Eventually, these conditions may lead to cervical cancer development.

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

“…The TLR4 signaling pathway is an emerging pathway related to tumor cell invasion and migration (11)(12)(13). TLR4 signaling has been shown to have oncogenic effects both in vitro and in vivo in various cancer types, including colon (14), breast (15), prostate (16), skin (17), ovarian (18), cervical (19), and esophageal (20) cancers, as well as HCC (21).…”

Tissue Microbiome Associated With Human Diseases by Whole Transcriptome Sequencing and 16S Metagenomics

“…The expression studies on cervical lesions to explore the possible relation of HPV with cervical cancer are also crucial. Toll-like receptor 4 (TLR4) expression supports the claim of a distinct relation between tumor formation and HPV-positive cervical cancer ( Jiang et al, 2020 ), suggesting that TLR4 somehow enables the formation of a local immunosuppressive microenvironment.…”

“…The relation between the vaginal microbiome ( Figure 1 ) and the high-risk HPV infection has been propounded by several studies ( Chao et al, 2019 , 2020 ; Keller et al, 2019 ; Liu et al, 2019 ; Nené et al, 2019 ; Zhou et al, 2019 ; Abudula et al, 2020 ; Jiang et al, 2020 ). The sequencing of 16S rRNA genes reveals that some anaerobic bacteria (e.g., Bacteroides plebeius and Acinetobacter lwoffii ) are significantly more common in HPV positive women, suggesting a specific microbiome as a biomarker to detect changes in the cervical microenvironment indicating HPV infection ( Chao et al, 2019 ).…”

TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line

“…In pancreatic tumors, LPS stimulates tumor development and increases invasiveness in vivo through activation of NF-κB via TLR4 signaling 29 . LPS treatment has also been implicated in the establishment of cervical tumors in a mouse model, while TLR4 silencing led to the formation of smaller tumors 30 .…”