Dual roles of WISP2 in the progression of hepatocellular carcinoma: implications of the fibroblast infiltration into the tumor microenvironment

Abstract

The dismal outcome of hepatocellular carcinoma (HCC) patients is attributable to high frequency of metastasis and. Identification of effective biomarkers is a key strategy to inform prognosis and improve survival. Previous studies reported inconsistent roles of WISP2 in carcinogenesis, while the role of WISP2 in HCC progression also remains unclear. In this study, we confirmed that WISP2 was downregulated in HCC tissues, and WISP2 was acting as a protective factor, especially in patients without alcohol intake using multiple online datasets. In addition, we reported that upregulation of WISP2 in HCC was related to inhibition of the malignant phenotype in vitro , but these alterations were not observed in vivo . WISP2 also negatively correlated with tumour purity, and increased infiltration of fibroblasts promoted malignant progression in HCC tissues. The enhanced infiltration ability of fibroblasts was related to upregulated HMGB1 after overexpression of WISP2 in HCC. The findings shed light on the anticancer role of WISP2, and HMGB1 is one of the key factors involved in the inhibition of the efficiency of WISP2 through reducing the tumour purity with fibroblast infiltration.

Expression and biological function of the cellular communication network factor 5 (CCN5) in primary liver cells

“…Actually, there is very little known about CCN5 biology in hepatic disease and the few previous articles available are somewhat inconsistent. CCN5 expression is lowered in HCC tumor tissues compared with normal tissue, while contrarily high CCN5 expression was associated with better prognosis in HCC, suggesting a dual role in CCN5 activity (Jia et al 2021). Possibly, these beneficial effects might be related to the fact that CCN5 promotes the homing of bone marrow‐derived mesenchymal stem cells, which promote liver regeneration and repair (Qin et al 2017).…”

“…CCN5 was shown to be lower expressed in several HCC cell lines and overexpression reduced migration, invasiveness, proliferation and the expression of epithelial‐to‐mesenchymal transition (EMT) markers, implying a protective role in vitro (Jia et al 2021). In contrast, high expression of CCN5 in vivo provokes enhanced infiltration of fibroblasts by triggering the expression of HMGB1 that weakens the anticancer effects (Jia et al 2021). In addition, CCN5 promotes liver repair by stimulating the in vivo homing of bone mesenchymal stem cells to the injured liver and stimulating endothelial cell proliferation and angiogenesis through modulating Cxcr4 signaling (Qin et al 2017).…”

“…However, in a recent study it was found that CCN5 was downregulated in HCC compared to normal adjacent tissue and this was coupled to poor prognosis. CCN5 was shown to be lower expressed in several HCC cell lines and overexpression reduced migration, invasiveness, proliferation and the expression of epithelial-to-mesenchymal transition (EMT) markers, implying a protective role in vitro (Jia et al 2021). In contrast, high expression of CCN5 in vivo provokes enhanced infiltration of fibroblasts by triggering the expression of HMGB1 that weakens the anticancer effects (Jia et al 2021).…”

TLR3 activation enhances sorafenib-antitumor effect in hepatocellular carcinoma by activating NK cell functions through ERK and NF-κB pathways

“…Western blot analysis with whole-cell extracts was performed essentially as previously described elsewhere 24 . Primary antibodies included anti-pERK1/2, anti-pAKT (Cell Signaling Technology; Danvers, MA, USA), anti-ERK1/2, and anti-AKT (Abcam; Cambridge, MA, USA)…”