TTF1 suppresses neuroblastoma growth and induces neuroblastoma differentiation by targeting TrkA and the miR-204/TrkB axis

Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children. We found that TTF1, TrkA, and miR-204 were lowly expressed, whereas TrkB was highly expressed in undifferentiated NB tissues. Meanwhile, TTF1 expression correlated positively with TrkA and miR-204 expression but negatively with TrkB expression. The TTF1 promoter was hypermethylated in undifferentiated NB tissues and SK-N-BE cells, leading to TTF1 downregulation. We also identified miR-204, which directly targets TrkB, as a transcriptional target of TTF1. Functionally, TTF1 suppressed proliferation, migration, and invasion of NB cells, whereas induced cell cycle arrest, apoptosis, and autophagy of NB cells by regulating TrkA and the miR-204-TrkB axis. Furthermore, TTF1 suppressed tumor growth and promoted neurogenic differentiation in a NB xenograft mouse model. Our study demonstrates that TTF1 reduces tumor growth and induces neurogenic differentiation in NB by directly targeting TrkA and the miR-204/TrkB axis.