Core fucosylated glycan-dependent inhibitory effect of QSOX1-S on invasion and metastasis of hepatocellular carcinoma

The goal of the present study was to identify glycoproteins associated with the postoperative relapse of hepatocellular carcinoma (HCC) and to investigate their potential role in HCC metastasis. A method for quantitating N-glycoproteome was used to screen for, and identify, recurrence-related N-linked glycoproteins from 100 serum samples taken from patients with early-stage HCC. The prognostic significance of candidate glycoproteins was then validated in 193 HCC tissues using immunohistochemical staining. Serum core fucosylated quiescin sulfhydryl oxidase 1 (cf-QSOX1) was identified as a leading prognostic glycoprotein that significantly correlated with HCC recurrence. Patients with high serum cf-QSOX1 levels had a significantly longer time to recurrence (TTR) as compared with those with low serum cf-QSOX1. As was seen with serum cf-QSOX1, QSOX1 in HCC tissues was further shown to be significantly associated with good patient outcome. Gain-functional and loss-functional analyses of QSOX1-S were performed in vitro and in vivo. QSOX1-S overexpression significantly increased in vitro apoptosis, but decreased the invasive capacity of HCC cells, and reduced lung metastasis in nude mice models bearing human HCC. Furthermore, overexpression of a mutant version of QSOX1-S, which had eliminated the core-fucosylated glycan at Asn-130, showed no demonstrable effect on invasion or metastasis of HCC cells. Our study suggests that serum cf-QSOX1-S and tumor QSOX1 levels are helpful for predicting recurrence in HCC patients, and its core-fucosylated glycan at Asn-130 is critical for the inhibitory effects of QSOX1-S on invasion and metastasis of HCC