In addition, Smad4 represses the expression of HPSE through directly binding to its promoter and attenuating lymphoid enhancer binding factor 1 (LEF1)-facilitated transcription of HPSE via physical interaction, thus suppressing the growth, invasion, metastasis and angiogenesis of NB cells in vitro and in vivo, suggesting the tumor suppressive roles of Smad4 in the progression of NB. The gene discussed is SMAD4; the disease is neuroblastoma.