Loss of αl,6‐fucosyltransferase inhibits chemical‐induced hepatocellular carcinoma and tumorigenesis by down‐regulating several cell signaling pathways

Up-regulation of core fucosylation catalyzed by α1,6-fucosyltransferase (Fut8) has been observed in hepatocellular carcinoma (HCC). Here, to explore the role of Fut8 expression in hepatocarcinogensis, we established the chemical-induced HCC models in the male wild-type (WT; Fut8+/+), hetero (Fut8+/-), and knockout (KO; mice by use of diethylnitrosamine (DEN) and pentobarbital (PB). In the Fut8+/+ and Fut8+/- mice, multiple large and vascularized nodules were induced with an increased expression of Fut8 after DEN and PB treatment. However, the formation of HCC in Fut8-/- mice was suppressed almost completely. This potent inhibitory effect of Fut8 deficiency on tumorigenesis was also confirmed by the abolished tumor formation of Fnt8 KO human hepatoma cell line cells by use of a xenograft tumor model. Furthermore, loss of the Fut8 gene resulted in attenuated responses to epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in the HepG2 cell line, which provides the possible mechanisms for the contribution of Fut8 to hepatocarcinogensis. Taken together, our study clearly demonstrated that core fucosylation acts as a critical functional modulator in the liver and implicated Fut8 as a prognostic marker, as well as a novel, therapeutic target for HCC.—Wang, Y., Fukuda, T., Isaji, T., Lu, J., Im, S., Hang, Q., Gu, W., Hou, S., Ohtsubo, K., Gu, J. Loss of α1,6-fucosyltransferase inhibits chemical induced hepatocellular carcinoma and tumorigenesis by down-regulating several cell signaling pathways. FASEB J. 29, 3217-3227 (2015). www.fasebj.org