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Molecular mechanism of activating protein-4 regulated growth of hepatocellular carcinoma
The molecular regulation of growth of hepatocellular carcinoma (HCC) is yet to be fully clarified. 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 tra...
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Published in: | Tumor biology 2014-12, Vol.35 (12), p.12441-12447 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The molecular regulation of growth of hepatocellular carcinoma (HCC) is yet to be fully clarified. 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. Moreover, strong correlations were detected between phos-β-cat/β-cat ratio and c-myc level, between c-myc and AP-4 levels, and between AP-4 and p21 levels. These data support the presence of a Wnt/c-myc/AP-4/p21 regulation cascade in HCC as has been reported in colorectal cancer. To prove it, we overexpressed c-myc in two HCC lines, which significantly increased AP-4 level, inhibited p21 level, and then increased cell growth. Meanwhile, c-myc inhibition in these two HCC lines significantly decreased AP-4 level, increased p21 level, and then decreased cell growth. Moreover, AP-4 inhibition in c-myc-overexpressing HCC lines abolished the inhibitory effect on p21 and abolished the increase in cell growth. In line with these findings, overexpression of AP-4 in these two HCC lines significantly decreased p21 level, and then increased cell growth, while AP-4 inhibition significantly increased p21 level, and then decreased cell growth. Our results on HCC are thus consistent with the model detected in colorectal carcinoma, suggesting that Wnt signaling activated c-myc may increase HCC growth through direct inhibitory effect of AP-4 on p21. Our study thus highlights AP-4 as a novel therapeutic target for HCC. |
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ISSN: | 1010-4283 1423-0380 |
DOI: | 10.1007/s13277-014-2562-0 |