Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils

Abstract

Background Long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP), has been demonstrated to be a vital biomarker when evaluating the prognosis of multiple cancers. Nevertheless, the potential function of HOTTIP in ovarian cancer (OC), a prevalent cancer among women worldwide, remains elusive. Hence, the current study aimed to elucidate the functional relevance of HOTTIP in the development of OC. Methods Positive expression of PD-L1 and IL-6 was determined using immunohistochemical staining in the collected OC and normal tissues. The correlation of IL-6 and PD-L1 was analyzed using flow cytometry, Western blot analysis as well as Pearson’s correlation coefficient. The interaction among HOTTIP, c-jun and IL-6 was investigated with the use of RIP, ChIP and dual luciferase reporter gene assays. Finally, the effects of HOTTIP on T cell proliferation and infiltration were identified through gain- and loss-of-function studies in vitro and in vivo. Results HOTTIP, IL-6 and PD-L1 were all highly expressed in OC tissues. A positive correlation was observed between IL-6 and PD-L1 and that between HOTTIP and IL-6 in OC tissues. HOTTIP was noted to promote the expression of IL-6 by binding to c-jun, which resulted in a promoted PD-L1 expression in neutrophils and immune escape while inhibiting T cell proliferation as well as tumor immunotherapy. Conclusion Taken together, our study unveiled that HOTTIP could promote the secretion of IL-6, and consequently up-regulate the expression of PD-L1 in neutrophils, thus inhibiting the activity of T cells and ultimately accelerating immune escape of OC cells. Our study provides a potential therapeutic strategy by targeting HOTTIP in OC.

Non-coding RNAs in Pancreatic Ductal Adenocarcinoma

“…HOTTIP interacts with the WD repeat containing protein 5 (WDR5)/mixed lineage leukemia (MLL) complex to enhance the methylation of histone 3 on lysine 4 (H3K4) in order to modulate the proliferation and differentiation of PDAC cells (36,37). Up-regulation of HOTTIP promotes the secretion of IL-6 and expression of PD-L1 in neutrophils, thereby inhibiting the activity of T cells and promoting the immune escape of ovarian cancer cells (38). This may be used for reference in immunotherapy of PDAC.…”

Basis of PD1/PD-L1 Therapies

“…For example, the lncRNA small nucleolar RNA host gene SNHG20 modulates the expression of PD-L1 and JAK2 in esophageal squamous cell carcinoma. Others include the lncRNAs HOTTIP [104], SNHG14 [105] and MALAT1 [106,107].…”

Six-lncRNA Immune Prognostic Signature for Cervical Cancer

“…In diffuse large B cell lymphoma, the lncRNA SNHG14 promotes tumor progression and immune escape by regulating the PD-1/PD-L1 checkpoints ( Zhao et al, 2019 ). In gastric cancer, the lncRNA HOTTIP has been reported to promote IL-6 expression, inhibit T cell proliferation and promote immune escape in gastric cancer cells ( Shang et al, 2019 ). UCA1 (another lncRNA) expression is elevated in gastric cancer, and UCA1 can inhibit miR-214 expression and upregulate PDL1 expression, thus contributing to immune escape in gastric cancer cells ( Wang C. J. et al, 2019 ).…”