Abstract
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
Highlights
Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide[1,2]
High serum levels of core-fucosylated QSOX1-S correlates with long time to recurrence (TTR) of patients after HCC
Kaplan–Meier analyses using the log-rank test revealed that serum cf-QSOX1 levels were significantly associated with TTR (P = 0.036) when the median expression level of serum cf-QSOX1 was used as the cutoff value (Fig. 1b)
Summary
Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide[1,2]. Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death Discovery (2019)5:84. The accumulating data strongly suggests that glycosylation may play fundamental roles in key pathological steps of tumor development and progression[8,9,10,11,12]. To this end, glycosylation has been shown to be involved in tumor cell–cell adhesion, cell–matrix interaction, cancer metabolism, and tumor immune surveillance[6]. The study strongly underscored the urgent need for more systematic analyses of glycosylation in clinical tumor samples[13]
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