Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis Through Epithelial-to-Mesenchymal Transition Pathway

Abstract

Over-expression of aspartyl (asparagynal)-β-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC.

Highlights

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  Over-expression of ASPH promoted HCC intrahepatic and distant metastases in vivo.

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  ASPH interacts with vimentin to promote HCC cell migration.

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  Enhanced hydroxylase activity in tumor predicted worse prognoses of HCC patients.

Hepatocellular carcinoma has aggressive invasiveness and high metastatic rate. The reason for metastasis is largely unknown and the effective treatment is still lacking. Although over-expression of ASPH has been demonstrated to enhance hepatocellular carcinoma invasiveness, whether its hydroxylase activity is necessary remains uncharacterized. Here, we found the hydroxylase activity was critical to promote hepatocellular carcinoma invasiveness in vitro and metastasis in vivo, and associated with post-surgery survival. ASPH hydroxylase activity play an important role in epithelial-to-mesenchymal transition through interacting with vimentin. Our findings imply that ASPH antagonists might be promising in developing novel therapy.