Dataset Information

Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.

ABSTRACT: Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage at which there are limited treatment options. Two recently identified human heparin-degrading endosulfatases, named sulfatase 1 (SULF1) and sulfatase 2 (SULF2), have been found to be involved in liver carcinogenesis. SULF1 and SULF2 desulfate cell surface and extracellular matrix heparan sulfate proteoglycans and modulate heparin-binding growth factor signaling in multiple cancers, including HCCs. SULF1 inhibits HCC tumor cell growth in vitro and in nude mice in vivo, partially through effects on gene expression mediated through histone H4 acetylation. While SULF1 is downregulated in the majority of HCC cell lines and approximately 30% of primary HCCs, SULF2 is upregulated in almost all HCC cell lines and in 60% of primary HCCs. In contrast to the tumor suppressor effect of SULF1, expression of SULF2 activates MAPK and Akt pathways, promotes HCC cell growth in vitro and in vivo, and is associated with decreased survival of HCC patients. Targeting SULF2 or the interaction between SULF2 and SULF1 may lead to novel therapeutics for the treatment of HCCs.

SUBMITTER: Lai JP

PROVIDER: S-EPMC3042146 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.

Lai Jin-Ping JP Thompson James R JR Sandhu Dalbir S DS Roberts Lewis R LR

Future oncology (London, England) 20081201 6

Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage at which there are limited treatment options. Two recently identified human heparin-degrading endosulfatases, named sulfatase 1 (SULF1) and sulfatase 2 (SULF2), have been found to be involved in liver carcinogenesis. SULF1 and SULF2 desulfate cell surface and extracellular matrix heparan sulfate proteoglycans and modulate heparin-binding growth factor signaling in multiple cancers, including HCCs. SULF1 inhibits HCC tumor cel ...[more]

PMID: 19086847

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Project description:BackgroundHepatocyte carcinoma (HCC) is one of the most common malignancies worldwide. Despite many achievements in diagnosis and treatment, HCC mortality remains high due to the malignant nature of the disease. Novel approaches, especially for targeted therapy, are being extensively explored. Gene therapy is ideal for such purpose for its specific expression of exogenous genes in HCC cells driven by tissue-specific promoter. However strategies based on correction of mutations or altered expressions of genes responsible for the development/progression of HCC have limitations because these aberrant molecules are not presented in all cancerous cells. In the current work, we adopted a novel strategy by targeting the DNA replication step which is essential for proliferation of every cancer cell.MethodsA recombinant adenovirus with alpha fetoprotein (AFP) promoter-controlled expressions of artificial microRNAs targeting DNA polymerases α, δ, ε and recombinant active Caspase 3, namely Ad/AFP-Casp-AFP-amiR, was constructed.ResultsThe artificial microRNAs could efficiently inhibit the expression of the target polymerases in AFP-positive HCC cells at both RNA and protein levels, and HCC cells treated with the recombinant virus Ad/AFP-Casp-AFP-amiR exhibited significant G0/1 phase arrest. The proliferation of HCC cells were significantly inhibited by Ad/AFP-Casp-AFP-amiR with increased apoptosis. On the contrary, the recombinant adenovirus Ad/AFP-Casp-AFP-amiR did not inhibit the expression of DNA polymerases α, δ or ε in AFP-negative human normal liver cell HL7702, and showed no effect on the cell cycle progression, proliferation or apoptosis.ConclusionsInhibition of DNA polymerases α, δ and ε by AFP promoter-driven artificial microRNAs may lead to effective growth arrest of AFP-positive HCC cells, which may represent a novel strategy for gene therapy by targeting the genes that are essential for the growth/proliferation of cancer cells, avoiding the limitations set by any of the individually altered gene.

Dataset Information

Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.

Publications

Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.

Similar Datasets

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