Su1004 High Mobility Group Box-1 Can Increase miR-21 Expression in Hepatocellular Carcinoma Through STAT3 Signaling

Abstract

Background and Aims: Using in vitro cell culture and in vivo xenograft mouse models, we have previously shown that the heparan sulfate-degrading endosulfatase SULF1 functions as a tumor suppressor in established hepatocellular carcinoma cell lines by abrogating receptor tyrosine kinase signaling. In contrast, whole genome gene expression analysis of resected human HCCs showed increased expression of SULF1 in 70% of primary HCCs; and SULF1 expression in primary HCCs has been associated with activation of the oncogenic Wnt/β-catenin pathway. Here we report for the first time the results of DEN-induced hepatocarcinogenesis in a hepatocyte-specific transgenic Sulf1 mouse model in which the Sulf1 gene is driven by the transthyretin promoter. The effect of Sulf1 transgenesis on Wnt/ β-catenin activation was assessed. Methods: Liver carcinogenesis was induced in wild-type or hepatocyte-specific Sulf1 transgenic mice by intraperitoneal injection of 15 mg/kg of the liver carcinogen diethylnitrosamine (DEN) at 14 days after birth. Mice were sacrificed at 8 months of age and the harvested livers were examined for weight, tumor size and number. Cell proliferation was assessed using the BrdU proliferation index and Wnt/ β-catenin activation was measured by assessment of β-catenin staining and cytoplasmic-nuclear translocation of β-catenin. Results: Consistent with the observation of increased SULF1 in primary human HCCs, Sulf1 transgenic mice showed increased liver tumorigenesis as demonstrated by tumor number, tumor volume, liver weight/body weight ratio, and BrdU proliferation index. To investigate the mechanism for this, we performed immunohistochemistry for β-catenin. Wnt-β-catenin signaling was increased in Sulf1 transgenic mice compared to wild-type mice, as assessed by both increased β-catenin immunostaining and increased cytoplasmic-nuclear translocation of β-catenin. Conclusions: In contrast to the tumor suppressor effects of SULF1 in established human cell lines, which are mediated by inhibition of the co-receptor function of heparan sulfate in receptor tyrosine kinase signaling, primary HCCs in an in vivo model of DEN-induced HCC in Sulf1 transgenic mice show increased liver tumorigenesis associated with activation ofWnt-β-catenin signaling. This suggests that the effect of Sulf1 in carcinogenesis is context-dependent, but appears to be mediated through oncogenic Wntβ-catenin signaling in the majority of HCCs.