Runt-related transcription factor 1 promotes apoptosis and inhibits neuroblastoma progression in vitro and in vivo

Abstract

Background: Runt-related transcription factor 1 (RUNX1) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters and can accelerate apoptosis in various tumors. However, the regulatory mechanisms underlying RUNX1 expression in neuroblastoma (NB), a highly malignant tumor in childhood, remain largely unclear. In this study, we aimed to assess the role of RUNX1 in NB and to reveal the underlying mechanisms that may contribute to finding a potential therapeutics strategy against NB. Methods: Growth, invasion, metastasis and angiogenesis were assessed using Cell Counting Kit-8 (CCK-8) immunocytochemistry, and studies involving soft agar, cell invasion, tube formation and whole animals. The levels of expression were measured using real-time quantitative PCR for RNA, Western blot and immunostaining analyses for proteins. Luciferase reporter and chromatin immunoprecipitation assays indicated that RUNX1 directly binds within the BIRC5, CSF2RB and NFKBIA promoter regions to facilitate transcription. The level of apoptosis was assessed by determining mitochondrial membrane potential and flow cytometry. Results: RUNX1 was highly expressed in ganglioneuroma (GN) and well-differentiated (WD) tissues relative to the poorly differentiated (PD) and undifferentiated (UD) ones. Moreover, RUNX1 effectively reduced cell viability, invasion, metastasis, angiogenesis, and promoted apoptosis in vitro and in vivo. RUNX1 reduced BIRC5 transcription and increased CSF2RB and NFKBIA transcription by directly binding BIRC5, CSF2RB and NFKBIA promoters. In addition, cytotoxic drugs, especially cisplatin, significantly increased RUNX1 expression in NB cells and promoted apoptosis. Conclusions: These data show that RUNX1 is an independent surrogate marker for the progression of NB and it can be used for monitoring NB prognosis during therapy.

RUNX1 is a promising prognostic biomarker and related to immune infiltrates of cancer-associated fibroblasts in human cancers

“…Several studies have demonstrated that RUNX1 expression is closely associated with the progression of solid tumors, such as ovarian cancer [ 9 ], glioblastoma [ 27 ], and renal cancer [ 28 ]. In contrast, RUNX1 overexpression has been linked to favorable outcomes and monitored prognosis during therapy in neuroblastoma [ 29 ]. RUNX1 expression can predict a better outcome for patients with prostate cancer, but plays a dual role in promoting or inhibiting the progression of this cancer [ 12 ].…”

CSF2RB Is a Unique Biomarker and Correlated With Immune Infiltrates in Lung Adenocarcinoma

“…GM-CSF, IL3, CSF2, and IL5 are important regulators of inflammation and immune suppression within the tumor microenvironment ( 23 ). They can produce proliferation and survival signals for many malignant tumors, such as leukemia, small cell lung cancer, melanoma, breast cancer, and prostate cancer ( 24 , 25 ). Hong et al.…”

“…Hong et al. found that the transcription factor RUNX1 could bind to the CSF2RB promoter to increase CSF2RB transcription, effectively reducing cell viability, invasion, metastasis, and angiogenesis and promoting neuroblastoma apoptosis in vitro and in vivo ( 24 ). Kao et al.…”

Integrative Identification of Hub Genes Associated With Immune Cells in Atrial Fibrillation Using Weighted Gene Correlation Network Analysis

“…The role of CSF2RB has been studied in many diseases. Runt-related transcription factor 1 directly bound to the promoters of CSF2RB , which regulated apoptosis of neuroblastoma ( 35 ). The activating hotspot mutation in CSFR2B was identified in myeloid leukemia in Down syndrome ( 36 ).…”