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

Abstract

Our previous studies showed that dysregulation of the long noncoding RNA (lncRNA) HOXA11-AS plays an important role in the development of glioma. However, the molecular mechanism of HOXA11-AS in glioma remains largely unknown. In this study, we explore the molecular mechanisms underlying abnormal expression and biological function of HOXA11-AS for identifying novel therapeutic targets in glioma. The expression of HOXA11-AS, and the relationship between HOXA11-AS and the prognosis of glioma patients were analyzed using databases and glioma samples. Transcriptomics, proteomics, RIP, ChIRP, luciferase, and ChIP assays were used to explore its upstream and downstream targets in glioma. The role of HOXA11-AS in regulating the sensitivity of glioma cells to reactive oxygen species (ROS) was also investigated in vitro and in vivo. We found that HOXA11-AS was significantly upregulated in glioma, and was correlated with the poor prognosis of glioma patients. Ectopic expression of HOXA11-AS promoted the proliferation, migration, and invasion of glioma cells in vitro and in vivo. Mechanistically, HOXA11-AS acted as a molecular sponge for let-7b-5p in the cytoplasm, antagonizing its ability to repress the expression of CTHRC1, which activates the β-catenin/c-Myc pathway. In addition, c-Myc was involved in HOXA11-AS dysregulation via binding to its promoter region to form a self-activating loop. HOXA11-AS, functioned as a scaffold in the nucleus, also recruited transcription factor c-Jun to the Tpl2 promoter, which activates the Tpl2-MEK1/2-ERK1/2 pathway to promote ROS resistance in glioma. Importantly, HOXA11-AS knockdown could sensitize glioma cells to ROS. Above, oncogenic HOXA11-AS upregulates CTHRC1 expression as a ceRNA by adsorbing let-7b-5p, which activates c-Myc to regulate itself transcription. HOXA11-AS knockdown promotes ROS sensitivity in glioma cells by regulating the Tpl2-MEK1/2-ERK1/2 axis, demonstrating that HOXA11-AS may be translated to increase ROS sensitivity therapeutically.

Leveraging a disulfidptosis‑related lncRNAs signature for predicting the prognosis and immunotherapy of glioma

“…Various studies indicate that biomarkers related to disulfidptosis have substantial predictive power for cancer prognosis and treatment efficacy [ 6 , 16 ]. Given the burgeoning evidence that lncRNA exerts a pivotal regulatory role in glioma growth and progression [ 38 ], DRLs should be assessed for their prognostic significance in glioma patients.…”

Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression

“…Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) assay (Apex Bio, TX, USA) following the manufacturer 92 . Briefly, control or NRBF2-deficient aNSCs were plated in a poly- L -ornithine/laminin-coated 96-well plate at a density of 5000 cells/well and treated with vehicle or bafilomycin A1 (20 nM) for 12 h. Then, CCK-8 was added, and the absorbance at 450 nm was detected using a microplate reader (Tecan, Männedorf, Switzerland).…”

The role and clinical relevance of long non-coding RNAs in glioma

“…Lastly, ADAMTS9-AS2, which is downregulated in glioblastoma and correlates with glioma grading, has been shown to inhibit cell migration and invasion upon overexpression [ 55 , 56 ]. Numerous studies are currently underway to develop a potential therapeutic approach based on interactions between lncRNAs and miRNAs, which reveal the vital role of this interaction in proliferation, angiogenesis, invasion, metastasis, cell survival and resistance to therapy in glioma ( Table 1 ) [ [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] ].…”

“… LncRNAs Expression of lncRNAs miRNAs Targets Function Ref. HOXA11-AS Up let-7b-5p Tpl2-MEK1/2-ERK1/2 axis Sensitizes glioblastoma cells to ROS, drastically impairing tumor growth and prolonging survival of mouses [ 57 ] MIR210HG Down miR-377–3p LMX1A Suppresses glioma cell proliferation [ 58 ] PDCD4-AS1 Down miR-30b-3p METTL7B Inhibits glioma cell proliferation, invasion, migration, and induces cell cycle arrest [ 59 ] GSCAR Down miR-6760–5p SRSF1 Promotes tumor cell responses to TMZ [ 60 ] SPRY4-IT1 Down miR-101–3p EZH2 and VEGFA Achieves cell proliferation and angiogenesis [ 61 ] LINC01018 Up miR-942–5p KNG1 Suppresses the migration, invasion, and proliferation of glioma cells [ 62 ] LINC01018 Up miR-182–5p ADRA2C, RAB6B, RAB27B, RAPGEF5, STEAP2, TAGLN3, and UNC13C Inhibits cell proliferation and metastasis [ 63 ] TUSC7 Up miR-10a-5p BDNF/ERK axis Suppre...…”