We show that in HCC but not in peritumoral tissue of the same HCC patients, Ln-5, Snail, and Slug are up-regulated, E-cadherin is down-regulated and beta-catenin is translocated into the nuclei.
The expression levels of CTNNB1 and MMP9 decreased by knocked down XRCC5 which may promote the progression of HCC via the Wnt/β-catenin signaling pathway.
Moreover, exogenous sFRP1 caused significant decrease of β-catenin/T-cell factor-dependent transcription activity.These findings demonstrate that sFRP1 silencing due to promoter hypermethylation is a major event during tumorigenesis. sFRP1 is also a negative modulator of canonical Wnt signaling, which could contribute to metastasis in HCC progression, thus providing a possible therapeutic strategy against HCC.
Clinicopathological parameters, progression-free survival (PFS) and overall survival (OS) were evaluated to analyze the association of β-catenin expression with prognosis for HCC patients after TACE.
<b>Rationale:</b> Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential.
These results indicate that the altered expression of beta-catenin in HCC may play an important role in tumor progression by stimulating tumor cell proliferation, and nonnuclear overexpression may have pathologic significance in HCC.
Aberrant activation of β-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression.
Immunohistochemical analysis was used to measure the expression of hepatocyte growth factor receptor (c-Met), β-catenin and focal adhesion kinase (FAK) in patients with HCC. c-Met expression was identified to be high in patients with larger tumors, higher α-fetoprotein (AFP) levels, higher Edmondson grades, portal vein invasion and higher tumor-node-metastasis (TNM) stages.
At difference with a number of epithelial cancers, vascular invasion was frequently noted in HCCs showing enforced expression of the membranous E-cadherin/beta-catenin complex.
Knockdown of YB-1 suppressed the expression of Wnt ligands and β-catenin, impaired Wnt/β-catenin signaling pathway and reduced the numbers of HCC initiating cells.
Here we found a significantly higher ratio of phosphorylated β-catenin (phos-β-cat) to β-catenin (β-cat) as an indicator of an activated Wnt signaling, with significantly higher levels of c-myc and transcription factor activating protein-4 (AP-4) and a significantly lower level of p21 in the resected HCC, compared to the paired adjacent healthy hepatic tissue from the patients.
The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs).
Reduction or loss of Wnt-5a protein expression was found in 80.7% of hepatocellular carcinoma cases (n=92) and was significantly associated with higher tumour stage (p<0.001), serum AFP level (p=0.025), low membranous expression of E-cadherin (p<0.0001) and beta-catenin (p=0.036) and high Ki-67 labelling indices (LIs, p=0.001).
In order to prove this hypothesis, 52 samples from human hepatocellular carcinomas were analysed for the activation of beta-catenin and the expression of GS.
Finally, Western blot results indicated that silencing FBXO17 might function through downregulating the expression of proteins in wnt/β-catenin pathway such as c-Myc, MMP-9, and MMP-2 while upregulating GSK-3β level, thereby promoting the malignant progression of HCC.
Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by ERK pathway, regulated β-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines.
On analyzing the relationship between alterations of beta-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that mutations of beta-catenin, as well as overexpression of beta-catenin or the Tcf-4 gene were independently correlated with C-myc gene overexpression in HCC.
We found that treatment with PGE2 significantly enhanced nuclear accumulation of β-catenin and the activation of GSK3β which could be reversed by meloxicam in HCC cells.