Expression of heparanase in human tumor cell lines and human head and neck tumors

Simizu, Siro; Ishida, Keisuke; Wierzba, Michal K; Sato, Taka Aki; Osada, Hiroyuki

doi:10.1016/s0304-3835(02)00719-x

Cited by 38 publications

(34 citation statements)

References 17 publications

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“…Similarly, the erroneous expression of HPSE by these cell types has been linked with restenosis and atherosclerotic disease (45). Recent studies (13,14) cells have demonstrated that elevated levels of HSPE protein, observed in highly invasive/metastatic tumors, correlate directly with increased levels of HPSE mRNA. This suggests that the control of HPSE expression at the transcriptional level is important in regulating HPSE function.…”

Section: Figmentioning

confidence: 99%

“…Indeed, substantial evidence has been generated using HPSE inhibitor studies (8 -10) and more recently with transfection approaches using HPSE sense (11), or antisense cDNA (12), that demonstrate a strong link between HPSE expression and experimental autoimmune disease or tumorigenesis. Furthermore, a high level of HPSE mRNA or protein expression has been shown to correlate with tumor invasion and metastasis (13)(14)(15) and a lower survival of cancer patients (16,17). These findings suggest that HPSE plays an important role in the migration of leukocytes to inflammatory sites and also in tumor invasion and metastasis.…”

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confidence: 93%

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Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

Mestre

Khachigian

Santiago

et al. 2003

Journal of Biological Chemistry

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Cleavage of heparan sulfate by the ␤-D-endoglucuronidase heparanase (HPSE) is a fundamental event in a number of important physiological processes including inflammation, wound healing, and angiogenesis. HPSE activity has also been directly correlated with pathological conditions such as tumor growth and metastasis and autoimmune disease. The tight regulation of HPSE expression and function is critical to ensure homeostasis of the normal physiological processes to which it contributes and to prevent imbalance toward pathological situations. Little is known about the transcriptional mechanisms that regulate HPSE expression. In this study we have shown human HPSE gene transcription in Jurkat T cells is induced upon activation. Functional analysis of the HPSE promoter has identified a 280-bp region that is highly inducible. Mutation studies together with supershift experiments have identified a 4-bp motif that binds the transcription factor early growth response-1 (Egr1) and is critical in regulating inducible HPSE gene transcription. Furthermore, the overexpression of Egr1 resulted in the enhanced activation of the HPSE promoter. By using MAPK pathway inhibitors, we have also shown that inducible expression of HPSE mRNA and the activity of the 280-bp HPSE promoter element are dependent on the ERK1/2 (MEK1/2) pathway. This pathway is critical for induction of Egr1 expression at both the mRNA and protein level in T cells, an observation that provides further support to Egr1 playing an important role as a key activator of HPSE expression. In addition, HPSE and Egr1 were shown to co-localize by immunohistochemistry to invading mononuclear leukocytes in actively induced experimental autoimmune encephalomyelitis in rats. These findings provide the first insight into the mechanisms controlling inducible transcription of the HPSE gene, and could represent an important lead into understanding how HPSE expression is deregulated in metastatic tumor cells.Heparan sulfate proteoglycans are key structural components of the extracellular matrix (ECM) 1 and cell surfaces. They comprise a protein core covalently linked to linear chains of the complex sulfated glycosaminoglycan, heparan sulfate (HS) (1-3). The HS side chains of heparan sulfate proteoglycans mediate the assembly and stability of the ECM through interactions with the various matrix components (e.g. collagen, laminin, and fibronectin) (1, 3) and also specifically bind a range of cytokines and growth factors (e.g. basic fibroblast growth factor, hepatocyte growth factor, insulin-like growth factor, and transforming growth factor-␤) thereby functioning as a storage depot for these factors (4, 5). The ␤-D-endoglycosidase heparanase (HPSE) cleaves HS and facilitates the degradation of the ECM and the release of HS-bound growth factors (6, 7). Heparanase is a normal constituent of activated leukocytes, endothelial cells, vascular smooth muscle cells, and cytotrophoblasts; however, its expression is also "hijacked" by metastatic tumor cells (6, 7). The level of HPSE activit...

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Section: Figmentioning

confidence: 99%

mentioning

confidence: 93%

Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

Mestre

Khachigian

Santiago

et al. 2003

Journal of Biological Chemistry

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“…[12][13][14][15][16] Since the first cloning of heparanase cDNA, overexpression of heparanase has been observed in many human tumors, such as head and neck tumors, 17) pancreatic tumors, 18) hepatocellular carcinoma, 19) esophageal carcinomas, 20) and cultured human tumor cell lines, 17,21) suggesting an involvement of heparanase in tumor progression. Thus, the compounds that block the heparanase active site, the ligand-binding domain, or the expression of heparanase are desired.…”

Section: -3)mentioning

confidence: 99%

“…Although the overexpression of heparanase mRNA and protein has been observed in many human tumor tissues, such as head and neck tumors, 17) pancreatic tumors, 18) hepatocellular carcinoma, 19) esophageal carcinomas, 20) and cultured human tumor cell lines, 17,21) heparanase mRNA was strictly expressed in the placenta and lymph nodes in normal tissues. 32) To identify the responsible transcriptional factor for the overexpression of heparanase mRNA in tumor cells, several groups have carried out promoter analyses of the heparanase gene.…”

Section: Heparanase Gene Expressionmentioning

confidence: 99%

“…38) Although the epigenetic inactivation of tumor suppressor genes has attracted much attention, the activation of tumor progression factors by aberrant hypomethylation has been documented in only a small number of loci to date. Given the involvement of heparanase in cancer metastasis and angiogenesis, Shteper et al 21) and our group 17) sought to identify an epigenetic mechanism that may regulate the expression of the heparanase gene. Treatment of low-level heparanase-expressing cells with a DNA methylation inhibitor, 5-aza-2′-deoxycytidine, resulted in an increase in heparanase mRNA.…”

Section: Heparanase Gene Expressionmentioning

confidence: 99%

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Heparanase as a molecular target of cancer chemotherapy

2004

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Cancer cells require the ability to degrade the extracellular matrix (ECM) in order to turn into invasive and metastatic cancer cells. Many proteases and glycosidases are essential in the process of dissolving the components of the ECM. An endo-β β β β-D-glucuronidase, heparanase, is capable of specifically degrading one of the ECM components, heparan sulfate, and this activity is associated with the metastatic potential of tumor cells. Since heparanase mRNA is overexpressed in many human tumors (e.g., hepatomas, head and neck tumors, and esophageal carcinomas), the mechanisms regulating the activity of heparanase should be clarified; considering the possible role of heparanase in cancer, the development of heparanase inhibitors would appear to be advantageous. This review will focus on recent findings that have contributed to the characterization of heparanase and to the elucidation of the transcriptional regulation of heparanase mRNA expression, as well as the development of heparanase inhibitors. tudies of the biological function of extracellular matrix (ECM) molecules have revealed the central role of heparan sulfate proteoglycans (HSPGs) in many biological events, such as early embryogenesis and angiogenesis.1, 2) Heparan sulfate (HS) chains, consisting of strongly anionic linear polysaccharides, are structurally heterogeneous and bind a diverse repertoire of proteins under physiological conditions. Cell surface HS provides cells with a mechanism to snare a wide variety of extracellular effectors. These cell surface HSPGs modulate the activity of a wide variety of HS-binding proteins, acting as coreceptors with signaling receptors and directly as endocytosis receptors.3) As co-receptors, they potentiate the activity of sparse ligands by enhancing the formation of ligand-receptor complexes. In addition, intracellular signaling and endocytosis are augmented when HSPGs interact with soluble ligands. 1-3)HS/HSPG is known to interact with various molecules, 3) such as growth factors (e.g., fibroblast growth factors), cytokines (e.g., interleukin-2), ECM proteins (e.g., collagens), factors involved in blood coagulation (e.g., heparin cofactor II), and other proteins such as β-amyloid proteins and matrix metalloproteinase-7.1, 2, 4) Since HS chains are very similar among organisms as diverse as insects, mollusks, and mammals, the conservation of HS binding to extracellular proteins suggests that the association of these proteins with HS is conserved and functionally relevant. Because of the important and pleiotropic roles of HSPGs in cell physiology, the cleavage of HSPGs is likely to alter the integrity and functional state of tissues and to provide a mechanism by which cells can respond rapidly to changes in the extracellular environment. HS/HSPG carbohydrate chains are cleaved either by lyases (eliminative cleavage) or hydrolases (hydrolytic cleavage). These cleaving enzymes are therefore in part responsible for the modulation of the biological functions of HS/HSPGs-binding proteins. The enzymatic degradation o...

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Mapping heparanase expression in the spinal cord of adult rats

Zhang¹,

Yeung²,

Li³

et al. 2005

J of Comparative Neurology

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This work addresses the cellular localization of heparanase and its colocalization with syndecan-3, a transmembrane heparan sulfate proteoglycan in spinal cords of adult rats. Reverse transcriptase/polymerase chain reaction (RT-PCR) and in situ hybridization for the heparanase transcript revealed expression in neurons and white matter glia. This was confirmed by immunohistochemistry showing cytoplasmic localization of the heparanase protein. Double immunofluorescence for heparanase and syndecan-3 revealed colocalization of the proteins in cell bodies of neurons and oligodendrocytes, suggestive of constitutive expression in these cell types. In contrast, only subpopulations of astrocytes and NG2-expressing glia in the white matter expressed heparanase, and these did not show expression of syndecan-3. Cultures of astrocytes further evidenced upregulation of heparanase expression with TGF-beta(1) treatment, but no accompanying upregulation of syndecan-3 was detectable. These first findings of heparanase expression in the adult cord therefore provide the cellular basis for understanding functional interactions of heparanase and syndecan-3 in the normal neural network or otherwise in glial reactions to spinal cord injury.

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Expression of heparanase in human tumor cell lines and human head and neck tumors

Cited by 38 publications

References 17 publications

Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

Heparanase as a molecular target of cancer chemotherapy

Mapping heparanase expression in the spinal cord of adult rats

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