Long Chain Non-Coding RNA HOTTIP Enhances IL-6 Expression to Promotes Immune Evasion of Ovarian Cancer Cells by Promoting the Expression of PD-L1 in Neutrophils

Abstract

HOXA transcript at the distal tip (HOTTIP), belonging to the family of long non-coding RNA (lncRNA), is an important biomarker for ovarian cancer (OC) prognosis. Nevertheless, the function of HOTTIP in immune evasion of OC cells remains undecided. In the current study, the effect of HOTTIP on the development of OC was assessed and the mechanism was discovered as well. The neutrophils were isolated from the clinical samples, and the correlation between programmed death-ligand 1 (PD-L1) and interleukin-6 (IL-6) in neutrophils was analyzed. The relationships among HOTTIP, c-jun and IL-6 were investigated by RIP, CHIP, and the dual luciferase reporter gene assay. The roles of PD-L1, IL-6 and HOTTIP on the T cell proliferation and infiltration were measured in vitro and in vivo. Moreover, the association between HOTTIP and IL-6 in OC tissue and the connection between HOTTIP and OC prognosis were evaluated. Positive relationships were observed between IL-6 expression in peripheral blood and the PD-L1 expression in neutrophils of OC patients, and between the HOTTIP and IL-6 expression in OC tissues. HOTTIP could induce the release of IL-6 via c-jun. Besides, HOTTIP boosted the PD-L1 expression in neutrophils and inhibited the T cell proliferation, thus potentiating the immune evasion of OC cells. The prognosis of patients with higher expression of HOTTIP was worse. In summary, the HOTTIP/IL-6/PD-L1 axis was demonstrates as a novel regulatory signaling pathway involving in the progression of OC. Funding Statement: This work is supported by National Natural Science Foundation of China (81472179, 81873975, 81808084), the Excellent Academic Leader Training Program of Shanghai Health System (2018BR31), the Fundamental Research Funds for the Central Universities (22120170071) and the Clinical Research And Cultivation Project of Shanghai Tongji Hospital (ITJ(ZD)1803). We would like to acknowledge the reviewers for their helpful comments on this paper. Declaration of Interests: The authors declare: None. Ethics Approval Statement: This study was permitted by the Ethics Committee of Tongji Hospital of Tongji University and The Sixth People’s Hospital of Yancheng City. Written informed consents were provided by all participants. All animal experiments were conducted under the review from the Animal Ethical and Experimental Committee of Tongji Hospital of Tongji University and The Sixth People’s Hospital of Yancheng City.