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Resveratrol could inhibit the growth of H22 tumor in Balb/c mice. The antitumor effect of resveratrol might be related to directly inhibiting the growth of H22 cells and indirectly inhibiting its potential effect on nonspecific host immunomodulatory activity.

Abstract. Hypoxia was shown to increase tumor cell invasion into the extracellular matrix in vitro. This result suggests that heparanase (Hpa), one of the key enzymes involved in tumor invasion and metastasis, may be regulated by hypoxia. RT-PCR, Western blot and Matrigel invasive assays were used to study the regulation of Hpa under hypoxia in human pancreatic MIA PaCa-2 cancer cells. Compared with those in normoxia (20% O 2 ), Hpa mRNA, protein and enzymatic activity levels, were up-regulated by a reduction in the oxygen level (1% O 2 ). Invasion by tumor cells into the extracellular matrix was found to be significantly enhanced. A reduction in Hpa protein levels was observed when nuclear factor κB (NF-κB) activation was blocked by pyrrolidine dithiocarbamate. The levels of Hpa were also reduced when Hpa was inhibited by an Hpa-specific antisense oligonucleotide. The MMP-9 mRNA, protein and gelatinase B activity levels in supernatants decreased significantly when Hpa was inhibited. We conclude that up-regulation of Hpa by hypoxia is NF-κB-dependent in MIA PaCa-2 cells and inhibition of Hpa reduces MMP-9 activity. This reduction in MMP-9 activity may be an important mechanism in tumor metastasis. IntroductionHeparanase (Hpa) is an endo-ß-glucuronidase that cleaves the heparin sulfate (HS) side-chain. This enzymatic reaction not only enhances tumor cell invasion and migration, but also releases important HS-binding cytokines relevant to angiogenesis, wound healing and tumor growth. Up-regulation of Hpa has been demonstrated in a number of primary human cancers and correlates with reduced postoperative survival in bladder (1), stomach (2), pancreas (3), colorectal (4) and gallbladder cancers (5). In addition, high levels of Hpa are expressed in patients with lymph nodes and distant metastasis (4-7).In solid tumors, cells are constantly exposed to chronic or acute hypoxia (8). In vitro studies have reported that tumor cells exposed to hypoxia exhibit an increased ability to invade the extracellular matrix (ECM) (9,10). Consequently, understanding the regulation and mutual relationship of degrading enzymes in hypoxic conditions is particularly important. It has been shown that high level of heparanase molecules may serve some species to adapt to severe hypoxic environment in spalax blind subterrance mole rat (11). In addition, a recent study showed that heparanase gene expression was increased in the brain tissue of rats subjected to repeated hypoxic exposures (12). Hpa activity was shown to be up-regulated by hypoxia in ovarian OC-MZ-6 cancer cell (13). However, information describing the mechanism of the regulation of Hpa and the relationship between degrading enzymes and hypoxia remains unresolved.In this study, we have characterized the regulation of Hpa in hypoxia using the human pancreatic cancer cell line MIA PaCa-2. The results showed that Hpa mRNA, protein and enzymatic activity levels were up-regulated by hypoxia, which is closely related to enhanced tumor cell invasion. Furthermore, up-regulation of Hpa ...

ANGPTL3 may be functionally involved in hepatocellular carcinoma cell proliferation and invasion and is a potential target for hepatocellular carcinoma therapy.

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