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World J Gastroenterol. Jan 21, 2010; 16(3): 306-311
Published online Jan 21, 2010. doi: 10.3748/wjg.v16.i3.306
Heparanase and hepatocellular carcinoma: Promoter or inhibitor?
Shuo Dong, Xiong-Zhi Wu, Zhong-Shan-Men In-patient Department, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300171, China
Author contributions: Dong S conducted the literature review and wrote the manuscript; Wu XZ provided guidance throughout the preparation of this manuscript, reviewed the text and made significant revisions to drafts of this manuscript.
Supported by National Natural Science Foundation of China, No. 30801495
Correspondence to: Dr. Xiong-Zhi Wu, Zhong-Shan-Men In-patient Department, Tianjin Medical University Cancer Institute and Hospital, Guang-Lin Road, He-Dong District, Tianjin 300171, China. ilwxz@163.com
Telephone: +86-22-23921723 Fax: +86-22-23537796
Received: June 23, 2009
Revised: September 28, 2009
Accepted: October 5, 2009
Published online: January 21, 2010

Abstract

Heparan sulphate proteoglycans (HSPGs) consist of a core protein and several heparan sulphate (HS) side chains covalently linked. HS also binds a great deal of growth factors, chemokines, cytokines and enzymes to the extracellular matrix and cell surface. Heparanase can specially cleave HS side chains from HSPGs. There are a lot of conflicting reports about the role of heparanase in hepatocellular carcinoma (HCC). Heparanase is involved in hepatitis B virus infection and hepatitis C virus infection, the activation of signal pathways, metastasis and apoptosis of HCC. Heparanase is synthesized as an inactive precursor within late endosomes and lysosomes. Then heparanase undergoes proteolytic cleavage to form an active enzyme in lysosomes. Active heparanase translocates to the nucleus, cell surface or extracellular matrix. Different locations of heparanase may exert different activities on tumor progression. Furthermore, enzymatic activities and non-enzymatic activities of heparanase may play different roles during HCC development. The expression level of heparanase may also contribute to the discrepant effects of heparanase. Growth promoting as well as growth inhibiting sequences are contained within the tumor cell surface heparan sulfate. Degrading different HSPGs by heparanase may play different roles in HCC. Systemic studies examining the processing, expression, localization and function of heparanase should shed a light on the role of heparanase in HCC.

Key Words: Apoptosis, Heparanase, Heparan sulphate, Hepatocellular carcinoma, Infection, Metastasis

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Extracellular matrix (ECM) remodeling plays an important role in the development of HCC[1].

Heparan sulphate proteoglycans (HSPGs), one of the main components of ECM, are abundant macromolecules associated with the cell surface and ECM of a wide range of cells of vertebrate and invertebrate tissues. The basic HSPG structure consists of a core protein and several heparan sulphate (HS) side chains covalently linked. Extracellular HSPGs can maintain the ECM self assembly and integrity with other macromolecules, while cell surface HSPGs may act as co-receptor for several signal pathway molecules. In fact, HS chains also bind a great deal of growth factors, chemokines, cytokines and enzymes to the ECM and cell surface. HSPGs can thus influence a number of normal and pathological processes, among which are tissue repair, inflammation, tumor growth and metastasis, and angiogenesis[2,3].

Recent discoveries indicated that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis[4,5]. Heparanase, an endoglycosidase, can specially cleave HS side chains from HSPGs and release a multitude of bioactive molecules. Then, the generated HS fragments and released bioactive mediators could facilitate tumor metastasis cooperatively. In addition, heparanase also exhibits non-enzymatic activities, including cell adhesion and survival, upregulation of vascular endothelial growth factor (VEGF) and tissue factor, induction of signal transduction, and enhancement of certain HSPG shedding from the tumor cell surface[6-16].

A large body of evidence suggest that the expression of heparanase in the tumor closely relates with the potential for tumor invasion, angiogenesis and metastasis in most tumors examined[7-10]. However, there are a lot of conflicting reports about the relationship between heparanase and HCC. It is timely to review the literature to evaluate the arguments for and against the possible roles of heparanase in HCC.

HEPARANASE AND HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) INFECTION

Cell surface heparan sulfate mediates entry and initiation of infection of HBV and HCV, the most important pathogenic factors for HCC. Proper structure and sulfation levels of heparan sulfate are prerequisite for this mediation[17-23]. Heparanase might inhibit HS-mediated HCV and HBV entry and the initiation of infection[18,21]. Degradation of cell surface heparan sulfate by pretreatment with heparanases resulted in a marked reduction of HCV envelope glycoprotein E2 binding to HepG2 cells[18]. Treatment of Namalwa B cells and human erythroleukemia K562 cells with heparinase I also reduced the cellular binding of HBV nucleocapsids[21]. However, HCV E2 bound to target cells via putative receptors in a noncompetitive manner. Incomplete inhibition of heparan sulfate might lead to a partial E2 blockade and evasion of the host immune response[23]. El-Assal et al[24] reported that heparanase expression was significantly higher in HCV-related HCC compared with that in HCV-negative patients. It is possible to assume that HCV enhances heparanase expression that may be involved in the HCV-related pathological and malignant changes.

HEPARANASE EXPRESSION IN LIVER DISEASES

A biphasic pattern of heparanase expression is also significantly observed in rat liver following partial hepatectomy, peaking at 12 h and 96-168 h and decreasing at 360 h post-surgery[25]. Elevated heparanase levels are noted in the early stages of thioacetamide induced rat liver fibrosis, with no further increase evident in rats exhibiting higher fibrotic grades[25]. Reduction or no significant difference in heparanase expression levels are found in liver fibrosis or cirrhosis samples resected from human patients[24,26-31].

There are conflicting reports about the expression level of heparanase in HCC. Examining HCC patients’ specimens by reverse transcriptase-polymerase chain reaction (RT-PCR) or Real-Time Quantitative RT-PCR, in situ hybridization, Western blotting, immunohistochemistry and tissue microarrays (TMAs), five out of the seven studies reported that heparanase was over-expressed in HCC[24,28-31]. However, two studies indicated that the expression level of heparanase was lower than that in adjacent noncancerous tissue[26,27] (Table 1).

Table 1 Studies examining the pro-metastatic role of heparanase in HCC.
StudiesNo.MethodsPositive rate of HCC tissueCorrelation between heparanase expression and HCC progression
El-Assal et al[24], 2001551RT-PCR47%Significant positive correlation
Ikeguchi et al[26], 2002502QRT-PCR< adjacent noncancerous tissueNo significant correlation
Ikeguchi et al[27], 2003482QRT-PCR< adjacent noncancerous tissueSignificant negative correlation
Xiao et al[28], 2003113QRT-PCR,WB, ISH, IHC> normal and cirrhosis tissueSignificant positive correlation
Chen et al[30], 2004332RT-PCR48.5%, > adjacent tissueSignificant positive correlation
Liu et al[31], 2005334RT-PCR48.5%, > paracancerous and normal tissueSignificant positive correlation
Chen et al[29], 20081205IHC in TMAs45.83%, > adjacent tumor tissue, cirrhosis, and normal liver tissueSignificant positive correlation
155 HCC tissue samples;
2Both HCC tissue samples and non-cancerous liver samples were obtained from the same patients;
316 normal liver tissue samples, 14 liver cirrhosis tissue samples and 11 HCC tissue samples;
4HCC tissue samples and paracancerous tissue samples were obtained from 33 HCC patients; paracancerous tissues of 9 cases of benign liver tumor were used as normal controls;
548 cases of adjacent HCC liver, 62 cases of cirrhosis, and 23 cases of normal liver tissues. HCC: Hepatocellular carcinoma; RT-PCR: Reverse transcriptase-polymerase chain reaction; QRT-PCR: Real-time quantitative RT-PCR; WB: Western blotting; ISH: In situ hybridization; IHC: Immunohistochemistry; TMAs: Tissue microarrays.
HEPARANASE AND HCC
Heparanase and metastasis of HCC

Metastasis is a sequential process including breaking off from the primary tumor, traveling through the bloodstream and stopping at a distant site. Heparanase enhances HCC metastasis by degrading ECM and releasing ECM-resident growth factors and angiogenic factors. Furthermore, non-enzymatic activities of heparanase, such as promoting cell adhesion, might also play a role in HCC metastasis[6-16].

Hepatoma heparanase was first purified from a human hepatoma cell line Sk-hep-1 in 1998[32]. El-Assal et al[24] reported that expression of heparanase mRNA was significantly correlated with larger tumor size, potential for tumor invasion and tumor microvessel density. Many research studies also support the concept that heparanase expression closely relates with metastasis and recurrence of HCC, tumor differentiation and tumor stage[28-31]. More recently, some researchers reported that down-regulating heparanase expression either by antisense oligodeoxynucleotide or by RNA interference could significantly inhibit the invasiveness, metastasis, and angiogenesis of human HCC SMMC7721 cells both in vitro and in vivo[33]. Yang et al[34] reported that two polypeptide antibodies, anti-MAP1 (multiple antigenic peptides)- and anti-MAP2-antibody, can effectively inhibit the heparanase activity of HCCLM6 human hepatocellular carcinoma cells in vitro and influence their invasive ability. Recently, PI-88, an heparanase inhibitor, showed preliminary efficacy as an adjunct therapy for post-operative HCC[35]. Glycosaminoglycan mimetics may also compete with cellular heparan sulfate chains for the binding to CXC-chemokine Stromal cell-Derived Factor-1 (SDF-1)/CXCL12 and may affect heparanase expression, leading to inhibition of SDF-1/CXCL12-mediated migration and invasion of the Huh7 human hepatoma cells[36].

However, Ikeguchi et al[26] reported that heparanase mRNA in HCC was significantly lower than that of noncancerous liver tissue and heparanase expression did not correlate with tumor differentiation, tumor stage, or patient prognosis. In another study conducted by Ikeguchi’s group, the expression level of heparanase was low in HCC and a high expression level of heparanase was associated with better disease-free 5-year survival rate[27]. Ogawa et al[37] established rat HCC cell lines with a high metastatic potential and found that one cell line, showing high levels of lung metastasis when injected subcutaneously in nude mice, exhibited decreased heparanase mRNA expression compared with other cell lines.

In a study of fibroblasts transfected with various oncogenes, one cell line exhibiting a metastatic phenotype was not found to have a significant increase in heparanase activities, though another one having the highest metastatic potential was shown to contain the greatest heparanase activity[38]. The hypothesis is that high heterogenicity of HCC might contribute to such discrepancy. Growth promoting as well as growth inhibiting sequences are contained within the tumor cell surface heparan sulfate[39]. Degrading different HSPGs by heparanase may play different roles in the complex process of metastasis.

Heparanase and apoptosis of HCC

The HS side chains of HSPGs could bind a multitude of growth factors, chemokines, cytokines and enzymes in ECM and cell surface, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor and hepatocyte growth factor. The cleaving of HSPGs by heparanase could release of HS-bound growth factors and exhibit complicated effects[7-10]. bFGF might enhance endothelial cell and tumor cell proliferation, contributing to HCC progression[40,41]. El-Assal et al[24] reported that bFGF and heparanase co-expressed in HCC patients’ specimen and this co-expression was associated with higher tumor microvessel density than that in specimens with expression of either factor alone.

Heparanase is involved in the activation of several signal pathways including bFGF-induced signal transduction[42-47] (Figure 1). In an in vitro study of melanoma cells, heparanase seemed necessary for phosphorylation of extracellular signal-related kinase (ERK) or focal adhesion kinase (FAK) in response to bFGF[46]. Kato et al[47] reported that in postmastectomy wound fluids, syndecan-1 was converted from an inhibitor to an activator of bFGF by the degrading activities of heparanase. The release of bFGF and HS degrading fragments by heparanase might promote bFGF-receptor binding and activation[42-47].

Figure 1
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Figure 1 Heparan sulphate proteoglycan (HSPG) and fibroblast growth factor (FGF)-induced signal transduction. Basic FGF (bFGF) enhances tumor progression by protecting tumor cells from apoptosis. Cell surface HSPGs could act as a co-receptor for formation of a bFGF high-affinity receptor complex. The alteration of cell surface HSPGs resulting from heparanase might down-regulate HSPG-mediated bFGF-induced signal pathway, resulting in apoptosis of tumor cells.

Heparanase expression closely related with apoptosis of several tumor cells, including HCC cells[27,48,49]. Ikeguchi et al[27] found a significant positive correlation between heparanase mRNA expression levels and the percentages of apoptotic hepatocytes in liver tissues. In addition to mitogenic effects, bFGF also could enhance some tumor progression by protecting tumor cells from apoptosis[50-56]. Targeting bFGF by neutralizing antibody or antisense oligonucleotides could result in apoptosis of some tumor cells[57-59]. Cell surface HSPGs could not only act as co-receptors for formation of bFGF high-affinity receptor complexes, but could also function directly as receptors for bFGF-induced signal transduction, depending on core protein or HS specific manner[60-62]. One possibility is that the alteration of cell surface HSPGs resulting from heparanase might down-regulate HSPG-mediated bFGF- induced signal pathways, resulting in apoptosis of tumor cells.

Location of heparanase in HCC

Human heparanase is synthesized as a 65 kDa inactive precursor within late endosomes and lysosomes. Then heparanase undergoes proteolytic cleavage, yielding 8 and 50 kDa protein subunits that heterodimerize to form an active enzyme in lysosome. Active heparanase translocates to the nucleus, cell surface or ECM[6,63]. Different locations of heparanase may exert different activities. Cell surface expression and secretion of heparanase in EB mouse lymphoma cells markedly promotes tumor angiogenesis and metastasis compared with intracellular enzyme[64]. However, nucleus heparanase induces differentiation of some tumor cells, such as esophageal cancer cells, mammary cancer cells and leukemic cells. Furthermore, a nuclear location of heparanase represents a better prognosis in tumor patients than its cytoplasmic location[65-70].

During liver regeneration, the location of heparanase exhibits a dramatic alteration from cytoplasm to cell surface in a time-dependant manner[25]. Xiao et al[28]and Chen et al[29] reported that high heparanase expression in HCC was localized within the cytoplasm of tumor cells and there was a significant correlation between the expression level of heparanase mRNA and tumor stage. Does the role of heparanase in HCC depend on its location

CONCLUSION

There are a lot of conflicting reports about the role of heparanase in HCC. Several questions are intriguing and shouldn’t be ignored. (1) In a human glioma cell xenograft tumor model, moderate heparanase expression levels significantly enhanced tumor development, whereas high heparanase expression levels inhibited tumor growth[71]. Another study also showed that extensive heparanase inhibited bFGF binding in human metastatic melanoma 70W cells, while treatment of 70W cells with low heparanase concentrations enhanced bFGF binding[46]. Does the effect of heparanase depend on its expression level in HCC (2) During the course of colon adenoma-carcinoma progression, active heparanase increases in the early stage, while latent heparanase predominantly increases in the late stage. The possibility was that enzymatic activities and non-enzymatic activities of heparanase have different roles in the early and late stages of colon cancer development[72]. Do enzymatic activities and non-enzymatic activities of heparanase play different roles during HCC development (3) HSPGs may have promoting or inhibiting activities depending on the core protein and localization[73]. For example, Glypican-3 and syndecan-1 might act as promoter and inhibitor during the development of HCC, respectively[74,75]. Degrading different HSPGs by heparanase may play different roles in HCC; and (4) Researchers have already observed that heparan sulfates could occur in hepatic nucleus and hypothesized that alteration of heparan sulfates detected in HCC might be involved in HS-related gene expression[76-81]. For example, DNA topoisomerase I activity is modulated by heparan sulfates present in normal liver cells but is markedly reduced or absent in their transformed counterparts[80]. Interestingly, active heparanase also could translocate to the nucleus and degrade nuclear HS[65-70,81]. Is heparanase the criminal for the lack of biologically active HS in HCC Do the effects of heparanase depend on its location in HCC Systemic studies examining the processing, expression, localization and function of heparanase should shed a light on the role of heparanase in HCC.

Footnotes

Peer reviewer: Matias A Avila, Professor and Senior Staff Scientist, Division of Hepatology and Gene Therapy, University of Navarra, Avda. Pio XII, n55, Pamplona, 31008, Spain

S- Editor Tian L L- Editor O'Neill M E- Editor Lin YP

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