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LIVER AND BILIARY TRACT

Thrombopoietin stimulates migration and activates multiple signaling pathways in hepatoblastoma cells

¹Dipartimento di Medicina Interna, University of Florence, Florence, Italy; ²Dipartimento di Medicina e Oncologia Sperimentale, University of Turin, Torino, Italy; ³Division of Hematology, Azienda Ospedaliera Careggi, Florence, Italy; and ⁴Center for Research, Transfer and High Education "Denothe," University of Florence, Florence, Italy

Submitted 3 August 2004 ; accepted in final form 24 August 2005

Thrombopoietin (TPO), a cytokine that participates in the differentiation and maturation of megakaryocytes, is produced in the liver, but only limited information is available on the biological response of liver-derived cells to TPO. In this study, we investigated whether HepG2 cells express c-Mpl, the receptor for TPO, and whether TPO elicits biological responses and intracellular signaling in this cell type. Specific transcripts for c-Mpl were detected in HepG2 cells by RT-PCR, and expression of the protein was demonstrated by Western blot analysis and immunofluorescence. Exposure of HepG2 cells to TPO was associated with a dose-dependent increase in cell migration and chemoinvasion through Matrigel-coated filters. A checkerboard analysis showed that the effects of TPO on cell migration were dependent on both chemotaxis and chemokinesis. Exposure of HepG2 cells to TPO resulted in the activation of different members of the MAPK family, including ERK and JNK, as assessed using phosphorylation-specific antibodies and immune complex kinase assays. TPO also activated phosphatidylinositol 3-kinase (PI3K) and the downstream kinase Akt in a time-dependent manner. Finally, activation of c-Mpl was associated with increased activation of nuclear factor-B. With the use of specific inhibitors, tyrosine phosphorylation and activation of PI3K were found to be required for the induction of migration in response to TPO. We conclude that TPO exerts biological actions on cultured hepatoblastoma cells via activation of c-Mpl and its downstream signaling.

Mpl; invasion; mitogen-activated protein kinases; phosphatidylinositol 3-kinase; nuclear factor-B; apoptosis

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