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)

Liver is the largest organ in the human body, and it regulates many physiological processes. Many studies on liver development in different model organisms have demonstrated that the mechanism of hepatogenesis is conserved in vertebrates. The identification of the genes and regulatory pathways involved in liver formation provides a basis for the diagnosis of liver diseases and therapeutic interventions. Hepatocellular carcinoma is the third leading cause of mortality worldwide. In the last decade, genetic alterations, which include the gain and loss of DNA, as well as mutations and epigenomic changes, have been identified as important factors in liver cancer. Many genetic pathways are dysregulated during carcinogenesis. Here, we review the gene regulatory networks that underlie liver organogenesis and the dysregulation of these pathways in liver cancer. The genes and pathways involved in hepatogenesis and liver cancer are largely conserved between zebrafish and humans, making this an ideal model organism for the study of this disease. A better understanding of liver development may aid in the development of new diagnostic and therapeutic approaches to liver cancer.

Our goal was to develop a fast-screening method for measuring dioxin levels in soils. The adenovirus (Ad)-dioxin-responsive (DR) bioassay system (AdEasy-6XDRE-TATA-Luc) combined with a fast-cleanup system was examined under conventional conditions (i.e., with incubation at 37°C) and three alternative conditions [incubation at 37°C with addition of phorbol-12-myristate-13-acetate (PMA), incubation at 33°C, and incubation at 33°C with addition of PMA]. The best conditions for carrying out the Ad-DR bioassay was 33°C and no addition of PMA. The background level of soil dioxins determined by the chemical assay [6.49 ng I-TEQ/kg dry weight (dw)] was well correlated (Pearson's r = 0.873, p < 0.001) with that by the Ad-DR bioassay [expressed in ng bioanalytical equivalents (BEQ) 81.1 ng BEQ/kg dw] (n = 17). When surveyed in contaminated soil samples (n = 114) from industrial areas by the Ad-DR bioassay, dioxin levels were 117, 102, 98.5, and 112 ng BEQ/kg dw, respectively, in northern, central, southern, and eastern Taiwan.