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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 (MAN1A, MAN1B, ERMAN1, MAN1C) 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 rates. 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.  MAN1A1  activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of  MAN1A1 ‐activated genes. 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 binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of  MAN1A1  activates the UPR and might initiate metastasis.  Conclusion : MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. ( Hepatology Communications  2017;1:230‐247)

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis