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Highlights • Knock-down on MYCN or LMO1 inhibited progression of neuroblastoma. • Decrease in FRS2 or let-7 level promoted MYCN and LMO1 expression. • Decrease in FRS2 or let-7 level promoted progression of neuroblastoma. • Inhibition on TGF-β1 signaling led to decreased expression of LMO1 but not MYCN. Abstract Background MYCN and LMO1 amplification are commonly observed in neuroblastoma (NB), which was often accompanied by genetic loss of let-7 microRNA (miRNA). Fibroblast growth factor (FGF) was found to regulate let-7 miRNA expression via FGF receptor substrate 2 (FRS2), which then activates transforming growth factor beta (TGF-β) signaling. Methods Expression of MYCN, LMO1, FRS2, let-7, and TGF-β receptor I (TGFβRI) was selectively knocked-down or enhanced in NB cells. Proliferation, invasion, migration, metastasis and tumorigenesis of NB, expression of downstream signaling factors and metastasis-associated protein were evaluated. Results Knock-down on either MYCN or LMO1 has led to inhibition on proliferation, invasion, migration, and metastasis of NB cells, and knock-down of FRS2 resulted in increases in MYCN and LMO1 expression and enhanced invasion, migration and metastasis of NB cells. Decreased expression of TGF-β1 or TGFβRI led to decrease expression in LMO1 and proliferation, invasion, migration and metastasis markers, except MYCN expression which appeared not to be regulated by TGF-β1 or TGFβRI. Furthermore, let-7 miRNA was shown to decrease the expression levels of TGF-βRI, LMO1 and MYCN. Conclusions FGF regulates MYCN and TGF-β1-induced LMO1 and metastasis of NB cells via let-7 miRNA. [ABSTRACT FROM AUTHOR]