LncRNA HOXA11-AS promotes gliomas malignant phenotypes and reduces its sensitivity to ROS via Tpl2-MEK1/2-ERK1/2 pathway

Background: Dysregulation of the long noncoding RNA (lncRNA) HOXA11-AS plays an important role in the development of gliomas. Hence, uncovering the molecular mechanisms underlying abnormal expression of lncRNAs is important for identifying novel therapeutic targets in glioma. Methods The expression of HOXA11-AS, and the relationship between HOXA11-AS and the prognosis of patients with glioma were analyzed using databases and glioma samples. CCK-8, EdU, wound healing, transwell, and subcutaneous xenograft assays were performed to study the effects of HOXA11-AS on the proliferation, migration, and invasion of glioma cells in vitro and in vivo . Transcriptomics, small RNA sequencing, RIP, ChIRP, luciferase, and ChIP assays were used to identify the relationship between HOXA11-AS and let-7b-5p, and to explore its downstream targets in glioma. The downstream targets of HOXA11-AS were explored using transcriptomic, proteomic, and bioinformatic analyses. The role of HOXA11-AS in reactive oxygen species (ROS) sensitivity in gliomas was determined by ROS sensitivity experiments and xenograft orthotopic model assays in vitro and in vivo . Results HOXA11-AS was significantly upregulated in gliomas, and was negatively correlated with the prognosis of patients with glioma. Ectopic expression of HOXA11-AS promoted the proliferation, migration, and invasion of glioma cells in vitro and in vivo . Mechanistically, HOXA11-AS competitively acts as a miRNA sponge by binding to let-7b-5p, to increase the expression of CTHRC1, which activates the β-catenin/c-Myc pathway. HOXA11-AS recruits c-Jun to the Tpl2 promoter to induce Tpl2 transcription, which activates the Tpl2-MEK1/2-ERK1/2 pathway to promote ROS resistance. HOXA11-AS knockdown increased ROS sensitivity of glioma cells. Conclusions HOXA11-AS upregulates CTHRC1 expression by binding to let-7b-5p, which promotes β-catenin nuclear accumulation and activates c-Myc to promote the transcription of HOXA11-AS itself. HOXA11-AS knockdown promotes ROS sensitivity in glioma cells by regulating the Tpl2-MEK1/2-ERK1/2 axis. Our results highlight the potential of HOXA11-AS as a biomarker and therapeutic target in gliomas.