RNA-binding protein DHX9 promotes glioma growth and tumor-associated macrophages infiltration via TCF12.

Background: Glioma is the most common malignant tumor of the central nervous system, with high heterogeneity, strong invasiveness, high therapeutic resistance, and poor prognosis, comprehending a serious challenge in neuro-oncology. Until now, the mechanisms underlying glioma progression have not been fully elucidated.

Methods: The expression of DExH-box helicase 9 (DHX9) in tissues and cells was detected by qRT-PCR and western blot. EdU and transwell assays were conducted to assess the effect of DHX9 on proliferation, migration and invasion of glioma cells. Cocultured model was used to evaluate the role of DHX9 on macrophages recruitment and polarization. Animal study was performed to explore the role of DHX9 on macrophages recruitment and polarization in vivo. Bioinformatics analysis, dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay was used to explore the relation between DHX9 and TCF12/CSF1.

Results: DHX9 was elevated in gliomas, especially in glioblastoma multiforme (GBM). Besides promoting the proliferation, migration, and invasion of glioma cells, DHX9 facilitated the infiltration of macrophages into glioma tissues and polarization to M2-like macrophages, known as tumor-associated macrophages (TAMs). DHX9 silencing decreased the expression of colony-stimulating factor 1 (CSF1), which partially restored the inhibitory effect on malignant progress of glioma and infiltration of TAMs caused by DHX9 knockdown by targeting the transcription factor 12 (TCF12). Moreover, TCF12 could directly bind to the promoter region of CSF1.

Conclusion: DHX9/TCF12/CSF1 axis regulated the increases in the infiltration of TAMs to promote glioma progression and might be a novel potential target for future immune therapies against gliomas.