4.8 Article

Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells

Journal

ONCOGENE
Volume 35, Issue 42, Pages 5468-5479

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.89

Keywords

-

Funding

  1. National Natural Science Foundation of China [31401222, 31571434, 31401190, 81172144]
  2. National Science and Technology Major Project [2012ZX10002-015, 2012AA020806, 2015CB553701]

Ask authors/readers for more resources

Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-beta 1-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-beta 1 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-beta 1 by activating beta-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-beta 1. The activated TGF-beta 1 signaling subsequently repressed the HNF4a 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-beta 1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-beta 1 and negatively correlated with HNF4a in human HCC tissues. Positive CD147 staining and lower HNF4a levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4a 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-beta 1-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-beta 1 and CD147.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available