HGF mediated downregulation of the novel gene MIA2 promotes progression of hepatocellular carcinoma

Recently, we identified a novel gene of the MIA gene family, Melanoma Inhibitory Activity 2 (MIA2) and found that MIA2 is selectively expressed in hepatocytes. In contrast, only low MIA2 expression levels were detected in most hepatocellular carcinomas (HCC) and HCC cell lines. Here, we aimed to determine the regulation and functional role of MIA2 in hepatocancerogensis and liver regeneration. In both conditions, hepatocyte growth factor (HGF) is known to be highly expressed and to play a central role, however, the underlying mechanism are still incompletely understood.

Methods and Results: By stable transfection MIA2 was re-expressed in HCC cell lines, and the generated cell clones were analyzed in vitro and in vivo. MIA2 re-expressing cell clones revealed a strongly reduced invasive potential and proliferation rate in vitro, and grew significantly slower in nude mice compared to mock transfected controls. In line with these findings treatment of HCC cells with recombinant MIA2 inhibited proliferation and migration. Immunohistochemical analysis of a tissue microarray containing HCC and non-cancerous liver tissue of 390 patients revealed reduced or complete lost MIA2 expression in 66% and 48% of HCC cases, respectively. In line with the in vitro data loss of MIA2 expression correlated significantly with the invasiveness of HCCs. In agreement with inhibition of proliferation by MIA2 in HCC we found strong downregulation of MIA2 expression during liver regeneration in mice following partial hepatectomy. In line with our previous finding that the transcription factor HNF–1 is mainly responsible for MIA–2 regulation, we found a significant correlation of MIA2 and HNF–1 expression in different HCC-tissue samples and -cells as well as in liver tissue during the course of liver regeneration. Since HGF is known to play an important role in both conditions we analyzed its effect on MIA2 and HNF–1 expression in vitro and in vivo. In primary human hepatocytes incubated with HGF as well as hepatic tissues of mice treated with HGF both MIA2 and HNF–1 expression were significantly inhibited.

Summary and Conclusion: This study presents MIA2 as an inhibitor of hepatocyte proliferation, and consequently, as a tumor suppressor of HCC. Further, we newly demonstrate that HGF inhibits hepatic HNF expression and show, that via this mechanism HGF suppresses hepatic MIA2 expression, indicating potentially new routes for therapy and diagnosis/prognosis of HCC.

HCC - HGF - MIA2