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

Ninghong Jiang; Feng Xie; Limei Chen; Fang Chen; Long Sui

doi:10.1186/s13027-020-0279-9

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

Infect Agent Cancer. 2020 Feb 17:15:12. doi: 10.1186/s13027-020-0279-9. eCollection 2020.

Authors

Ninghong Jiang^{1

2}, Feng Xie^{1

2}, Limei Chen^{1

2}, Fang Chen^{1

2}, Long Sui^{1

2}

Affiliations

¹ 1Medical center for diagnosis and treatment of cervical disease, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011 China.
² Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011 China.

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 × 10⁷/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.

Keywords: Cervical cancer; HPV; Local inflammatory microenvironment.