Abstract
α-1,2 mannosidases, key enzymes in N-glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α-1,2 mannosidases can result in cancer although the underlying mechanisms are unclear. Here we report the distinct roles of α-1,2 mannosidase subtypes in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α-fetoprotein level and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels, combined with low MAN1C1 expression levels, were significantly correlated with shorter overall survival rate. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation- and migration was increased in MAN1A1-overexpressing cells but decreased in MAN1C1-overexpressing cells. Besides, MAN1A1 activated the expression of key regulators of the unfolded protein response while treatment with ER stress inhibitors blocked the expression of MAN1A1-activated genes. Consequently, using the MAN1A1 liver-specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator, BiP. These data suggest that the up-regulation of MAN1A1 activates UPR and might initiates metastasis. Together our study demonstrates that MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis.