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

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

Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation

“…In this study, we demonstrated a previously unknown function of QSOX1 that effectively impairs the antioxidant capacity of HCC cells and thus increases their sensitivity to oxidative stress. These findings provide a mechanistic basis for previous observations by our group identifying QSOX1 as a potential tumor suppressor in HCC [ 20 ]. Parallel studies have suggested that QSOX1 may also act as a pro-oncogenic gene that promotes malignant phenotypes in some types of cancer [ 29 , 30 ].…”

“…S5 ). Our previous work had suggested that QSOX1 could inhibit EGFR signaling in HCC cells [ 20 ]. Several studies have also linked EGFR signaling to activation of NRF2 [ 16 ].…”

“…Human lentiviral shRNA against human QSOX1 was designed as previously described [ 20 ]. pLenO-DCE-puro vector was used for QSOX1 overexpression.…”

“…QSOX1 mainly localizes to the Golgi apparatus and intracellular vesicles, suggesting a potential role in intracellular vesicle transport. In a previous study we identified QSOX1 as a tumor suppressor in HCC [ 20 ]. We found that QSOX1 can inhibit EGFR signaling and suppress the invasive and metastatic capacity of HCC cells.…”

Recent Advances of Functional Proteomics in Gastrointestinal Cancers- a Path towards the Identification of Candidate Diagnostic, Prognostic, and Therapeutic Molecular Biomarkers

“…Further functional analysis showed that overexpression of QSOX1 increased apoptosis and decreased the invasive capacity of HCC cells and lung metastasis in nude mice models with HCC. Furthermore, core-fucosylated glycan at Asn-130 was shown to be essential for inhibitory effect of QSOX1 on the invasive and metastatic potential of HCC [ 78 ].…”