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DNA methylation-mediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by α3β1 integrin-Rho GTPase signaling.

Fu Y, Feng MX, Yu J, Ma MZ, Liu XJ, Li J, Yang XM, Wang YH, Zhang YL, Ao JP, Xue F, Qin W, Gu J, Xia Q, Zhang ZG - Oncotarget (2014)

Bottom Line: 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.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 α3β1 integrin.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. These authors contributed equally to this work.

ABSTRACT
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 α3β1 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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Detailed characterization of DPT expression in normal liver, paracancerous liver (PCL), hepatocellular carcinoma (HCC) and thrombus tissues from the same individual patients (n=6)(A) Immunohistochemical staining of DPT in HCC, PCL, normal liver and thrombus tissues. Scale bars, 10 μm. (B) Relative mRNA expression of DPT in HCC, PCL, normal liver and thrombus tissues. (C) Western blotting analysis of DPT expression in HCC, PCL, normal liver and thrombus tissues. Values were normalized to GAPDH.
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Figure 2: Detailed characterization of DPT expression in normal liver, paracancerous liver (PCL), hepatocellular carcinoma (HCC) and thrombus tissues from the same individual patients (n=6)(A) Immunohistochemical staining of DPT in HCC, PCL, normal liver and thrombus tissues. Scale bars, 10 μm. (B) Relative mRNA expression of DPT in HCC, PCL, normal liver and thrombus tissues. (C) Western blotting analysis of DPT expression in HCC, PCL, normal liver and thrombus tissues. Values were normalized to GAPDH.

Mentions: To further assess the relationship between the expression level of DPT and HCC metastasis, we collected normal liver, PCL, HCC and tumor thrombus tissues from the same individual patients and performed immunohistochemical staining. A higher DPT expression level was detected in the normal liver and PCL tissues compared to the HCC and tumor thrombus tissues (Figure 2A), which was confirmed by qPCR (Figure 2B) and western blotting (Figure 2C). These data further indicate that DPT may play an important role in modulating the invasiveness and metastasis of HCC.


DNA methylation-mediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by α3β1 integrin-Rho GTPase signaling.

Fu Y, Feng MX, Yu J, Ma MZ, Liu XJ, Li J, Yang XM, Wang YH, Zhang YL, Ao JP, Xue F, Qin W, Gu J, Xia Q, Zhang ZG - Oncotarget (2014)

Detailed characterization of DPT expression in normal liver, paracancerous liver (PCL), hepatocellular carcinoma (HCC) and thrombus tissues from the same individual patients (n=6)(A) Immunohistochemical staining of DPT in HCC, PCL, normal liver and thrombus tissues. Scale bars, 10 μm. (B) Relative mRNA expression of DPT in HCC, PCL, normal liver and thrombus tissues. (C) Western blotting analysis of DPT expression in HCC, PCL, normal liver and thrombus tissues. Values were normalized to GAPDH.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196157&req=5

Figure 2: Detailed characterization of DPT expression in normal liver, paracancerous liver (PCL), hepatocellular carcinoma (HCC) and thrombus tissues from the same individual patients (n=6)(A) Immunohistochemical staining of DPT in HCC, PCL, normal liver and thrombus tissues. Scale bars, 10 μm. (B) Relative mRNA expression of DPT in HCC, PCL, normal liver and thrombus tissues. (C) Western blotting analysis of DPT expression in HCC, PCL, normal liver and thrombus tissues. Values were normalized to GAPDH.
Mentions: To further assess the relationship between the expression level of DPT and HCC metastasis, we collected normal liver, PCL, HCC and tumor thrombus tissues from the same individual patients and performed immunohistochemical staining. A higher DPT expression level was detected in the normal liver and PCL tissues compared to the HCC and tumor thrombus tissues (Figure 2A), which was confirmed by qPCR (Figure 2B) and western blotting (Figure 2C). These data further indicate that DPT may play an important role in modulating the invasiveness and metastasis of HCC.

Bottom Line: 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.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 α3β1 integrin.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. These authors contributed equally to this work.

ABSTRACT
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 α3β1 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.

Show MeSH
Related in: MedlinePlus