Journal
ONCOTARGET
Volume 5, Issue 16, Pages 6701-6715Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2239
Keywords
Dermatopontin; Hepatocellular Carcinoma; Patient prognosis; Methylation; Metastasis; alpha 3 beta 1 integrin
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Funding
- National Key Sci-Tech Special Projects of Infectious Diseases [2013ZX10002-007-006]
- National Science Foundation of China [81071738, 81101600, 81201624, 81372368]
- Innovation Program of Shanghai Municipal Education Commission [12YZ043]
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Dermatopontin (DPT), a tyrosine-rich, acidic matricellular protein, has been implicated in several human cancers. However, its biological functions and molecular mechanisms in cancer progression, particular hepatocellular carcinoma (HCC), remain unknown. We demonstrated that DPT was significantly down-regulated in 202 HCC clinical samples and that its expression level was closely correlated with cancer metastasis and patient prognosis. The overexpression of DPT dramatically suppressed HCC cell migration in vitro and intrahepatic metastasis in vivo. We further revealed that the down-regulation of DPT in HCC was due to epigenetic silencing by promoter DNA methylation. And the inhibitory effects of DPT on HCC cell motility were associated with dysregulated focal adhesion assembly, decreased RhoA activity and reduced focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src) phosphorylation, and all of these alterations required the involvement of integrin signaling. Furthermore, we determined that the inhibitory effects of DPT on HCC cell motility were primarily mediated through alpha 3 beta 1 integrin. Our study provides new evidence for epigenetic control of tumor microenvironment, and suggests matricellular protein DPT may serve as a novel prognostic marker and act as a HCC metastasis suppressor.
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