| First Author | Wu J | Year | 2016 |
| Journal | Oncogene | Volume | 35 |
| Issue | 42 | Pages | 5468-5479 |
| PubMed ID | 27041581 | Mgi Jnum | J:287722 |
| Mgi Id | MGI:6423194 | Doi | 10.1038/onc.2016.89 |
| Citation | Wu J, et al. (2016) Regulation of a TGF-beta1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells. Oncogene 35(42):5468-5479 |
| abstractText | Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-beta1-CD147 self-sustaining network in the regulation of the dedifferentiation progress was fully explored in HCC cell lines, hepatocyte-specific basigin/CD147-knockout mice and human HCC tissues. We demonstrated that TGF-beta1 stimulation upregulated CD147 expression and mediated the dedifferentiation of HCC cells, whereas all-trans-retinoic acid induced the downregulation of CD147 and promoted differentiation in HCC cells. Overexpression of CD147 induced the dedifferentiation and enhanced the malignancy of HCC cells, and increased the transcriptional expression of TGF-beta1 by activating beta-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-beta1. The activated TGF-beta1 signaling subsequently repressed the HNF4alpha expression via Smad-Snail1 signaling and enhanced the dedifferentiation progress. Hepatocyte-specific basigin/CD147-knockout mice decreased the susceptibility to N-nitrosodiethylamine-induced tumorigenesis by suppressing TGF-beta1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-beta1 and negatively correlated with HNF4alpha in human HCC tissues. Positive CD147 staining and lower HNF4alpha levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4alpha and Smad7 and the deletion of CD147 by lentiviral vectors jointly reprogrammed the expression profile of hepatocyte markers and attenuated malignant properties including proliferation, cell survival and tumor growth of HCC cells. Our results highlight the important role of the TGF-beta1-CD147 self-sustaining network in driving HCC development by regulating differentiation plasticity, which provides a strong basis for further investigations of the differentiation therapy of HCC targeting TGF-beta1 and CD147. |
