FGF represses metastasis of neuroblastoma regulated by MYCN and TGF-β1 induced LMO1 via control of let-7 expression

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.

Keywords: FRS2; LMO1; MYCN; Neuroblastoma; TGFβRI; let-7 miRNA.