TGF-beta induces epithelial-mesenchymal transition, which occurs during tumor cell invasiveness in pathological state, in limited cells. As a first step to understand the role of TGF-beta and the structurally related activin during melanoma metastasis, expression of metastasis-related genes was examined in murine melanoma cells. Treatment with TGF-beta1 or activin A down-regulated E-cadherin in B16 cells in a dose-dependent manner. In epithelial cells, TGF-beta-induced high mobility group A2 (HMGA2) gene product is suggested to down-regulate E-cadherin through up-regulation of zinc-finger transcription factors Slug and Snail, and basic helix-loop-helix transcription factor Twist. Unlike the regulation in epithelial cells, TGF-beta1 treatment rather decreased mRNA expression of HMGA2, indicating a distinct mechanism on TGF-beta/activin-induced down-regulation. Transfection of double-stranded interfering RNA (dsRNAi) for activin receptor-like kinase (ALK) type I receptors revealed that ALK5, a prototype of TGF-beta receptor, mainly transmits TGF-beta signals on the E-cadherin down-regulation at the mRNA level, and that a prototype receptor ALK4 elicited the activin effect. TGF-beta/activin potentiated down-regulation of E-cadherin and HMGA2 also in B16 sublines that are susceptible to metastasis. However, the extent of down-regulation tended to be smaller, and less Smad2, a signal mediator for TGF-beta/activin, was phosphorylated in response to the ligand, resulting from less expression of type I receptors in the B16 sublines. These results suggest that the receptor expression level determines strength of the signals for TGF-beta/activin through phosphorylation of Smad2, which explains pluripotency of the ligand family partly.
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