Abstract
Overexpressed EphB4 conduce to tumor development and is regarded as a potential anticancer target. Homoharringtonine (HHT) has been approved for hematologic malignancies treatment, but its effect on hepatocellular carcinoma (HCC) has not been studied. This study elucidated HHT could restrain the proliferation and migration of HCC via an EphB4/β-catenin-dependent manner. We found that the antiproliferative activity of HHT in HCC cells and tumor xenograft was closely related to EphB4 expression. In HepG2, Hep3B and SMMC-7721 cells, EphB4 overexpression or EphrinB2 Fc stimulation augmented HHT-induced inhibitory effect on cell growth and migration ability, and such effect was abrogated when EphB4 was knocked down. The similar growth inhibitory effect of HHT was observed in SMMC-7721 and EphB4+/SMMC-7721 cells xenograft in vivo. Preliminary mechanistic investigation indicated that HHT directly bound to EphB4 and suppressed its expression. Data obtained from HCC patients revealed increased β-catenin expression and a positive correlation between EphB4 expression and β-catenin levels. HHT-induced EphB4 suppression promoted the phosphorylation and loss of β-catenin, which triggered regulation of β-catenin downstream signaling related to migration, resulting in the reversion of EMT in TGF-β-induced HepG2 cells. Collectively, this study provided a groundwork for HHT as an effective antitumor agent for HCC in an EphB4/β-catenin-dependent manner.
Highlights
Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with poor prognosis and an increasing incidence[1]
HHT exhibited a growth inhibitory effect on hepatocellular carcinoma (HCC) cells in vitro and in vivo To determine the effect of HHT on the cell viability of HCC cells, several different HCC cells HepG2, Bel-7402, Hep3B, and SMMC-7721 were treated with an increased gradient of HHT for 48 h
Similar result was observed in wound healing assay, which demonstrated that both transfection with Erythropoietin-producing hepatocyte receptor B4 (EphB4) and exogenous stimulation with soluble EphrinB2 Fc in SMMC-7721 cells delayed the closure of wound gaps following HHT treatment (Fig. 3b, d). These results indicated that the suppression of HHT on HCC cells migration was closely associated with EphB4 expression
Summary
Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with poor prognosis and an increasing incidence[1]. The major therapeutic approaches such as surgical resection, radiation therapy, and chemotherapy have advanced clinical applications, the 5-year survival rate of HCC remains less than 30%2. Most patients still suffer from tumor recur, invasiveness, and metastasis. Sorafenib, a multiple tyrosine kinase inhibitor, is one of the most representative options for advanced HCC, but is sometimes limited and accompanied with reduced sensitivity and severe adverse events[3,4]. Much effort is needed on this front to uncover new anti-HCC therapeutic strategies[5]
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