The significance of EphA2-regulated Wnt/β-catenin signal pathway in promoting the metastasis of HBV-related hepatocellular carcinoma.

Hepatitis B virus (HBV) infection is closely associated with the malignant progression of hepatocellular carcinoma (HCC). However, the mechanism involved in the HBV-related HCC development remains poorly understood. Hence, the aim of this study is to investigate the regulatory mechanism of EphA2-induced epithelial-mesenchymal transition (EMT) in the metastasis of HBV-related HCC cells. The expression level of EphA2 was determined in HBV-related human HCC cells. Then, the effects of EphA2 silencing on the EMT-associated proteins, the Wnt/β-catenin signal pathway and the metastatic potential of HBV-related HCC cells were evaluated. Finally, the inhibitory role of Entecavir (a potent antiviral drug for HBV) on EphA2-induced EMT was explored. The present study revealed that the EphA2 expression level was increased in HBV-related HCC cells compared with non-related HCC cells. Following EphA2 knockdown, the downregulation of Vimentin, β-catenin and p-GSK-3βSer9 expressions, the upregulation of E-cadherin expression, and the suppressed migration and invasion ability of HBV-related HCC cells were found. Additionally, Entecavir was proved to have a significant inhibitory effect on EphA2-induced EMT via attenuating the Wnt/β-catenin signal pathway. In this study, we found that EphA2-induced EMT was involved in the enhanced metastatic potential of HBV-related HCC cells through the activation of the Wnt/β-catenin signal pathway.

Wang Y ，Zhang Z ，Zhu Z ，Wang P ，Zhang J ，Liu H ，Li J ... -  《-》

HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway.

HBx mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development of HCC. However, activation of the Wnt/β-catenin signaling pathway by HBx mutants has not been studied in hepatoma cells or HBV-associated HCC samples. In this study, we examined the effects of HBx mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β-catenin signaling in HBx-transfected HCC cells and HBV-related HCC tissues. We found that HBx mutants (T, A, TA, and Combo) promoted the migration and proliferation of hepatoma cells. The HBx Combo mutant potentiated TOP-luc activity and increased nuclear translocation of β-catenin. Moreover, the HBx Combo mutant increased and stabilized β-catenin levels through inactivation of glycogen synthase kinase-3β, resulting in upregulation of downstream target genes such as c-Myc, CTGF, and WISP2. Enhanced activation of Wnt/β-catenin was found in HCC tissues with HBx TA and Combo mutations. Knockdown of β-catenin effectively abrogated cell migration and proliferation stimulated by the HBx TA and Combo mutants. Our results indicate that HBx mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV-associated hepatocarcinogenesis.

Chen Z ，Tang J ，Cai X ，Huang Y ，Gao Q ，Liang L ，Tian L ，Yang Y ，Zheng Y ，Hu Y ，Tang N ... -  《-》

miR-557 inhibits hepatocellular carcinoma progression through Wnt/β-catenin signaling pathway by targeting RAB10.

Cheng X ，Wu C ，Xu H ，Zou R ，Li T ，Ye S ... -  《Aging-US》

A novel O(2)- (2,4-dinitrophenyl) diazeniumdiolate inhibits hepatocellular carcinoma migration, invasion, and EMT through the Wnt/β-catenin pathway.

Targeted Wnt/β-catenin pathway is considered to be a promising therapy for cancer metastasis. The novel O2 -(2,4-dinitrophenyl) diazeniumdiolate (JS-K) plays a potent inhibitory role in the proliferation of cancers. In this study, HepG2 and SMMC7721 were used to clarify the efficacy of JS-K inhibition of HCC metastasis. JS-K significantly inhibited cell motility through a wound-healing assay and restrained cell migration and invasion at noncytotoxic concentrations. However, the inhibitory effects of migration and invasion were abolished after the addition of NO scavenger, Carboxy-PTIO. In addition, JS-K inhibited the Wnt/β-catenin pathway by a decrease of p-GSK-3β at Ser9, cytosolic β-catenin, and nuclear β-catenin accumulation whereas an increase of p-β-catenin. Furthermore, the transcription regulators c-Myc, survivin, and Cyclin D1 were down-regulated after treating with JS-K. The inhibitory of the Wnt/β-catenin pathway was reversed after the addition of Carboxy-PTIO or LiCl. Meanwhile, JS-K also inhibited the epithelial-mesenchymal transition (EMT)-mediated cell migration and invasion. The characteristics of the inhibition were reflected by the upregulation of E-cadherin whereas the downregulation of Vimentin, Snail, and Slug. Taking together, these results demonstrated that JS-K inhibited HepG2 and SMMC7721 cells migration and invasion by reversing EMT via the Wnt/β-catenin pathway.

Xing Y ，Hu Y ，Zou H ，Xie H ，Jiang T ，Liu L ... -  《-》

MicroRNA-338 inhibits proliferation, migration, and invasion of gastric cancer cells by the Wnt/β-catenin signaling pathway.

Song B ，Lin HX ，Dong LL ，Ma JJ ，Jiang ZG ... -  《-》