Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of E-cadherin (E-cad) triggers invasion, metastasis, and dedifferentiation in various epithelial carcinomas. Recently, it has been reported that two transcription factors, Snail and SIP1 (Smad interacting protein 1), directly repress transcription of the E-cad gene by binding E-box on E-cad promoter. Our aim is to solve the molecular mechanism of Snail and SIP1 in hepatocellular carcinoma (HCC). We first showed an inverse correlation between E-cad and Snail/SIP 1 expression among five HCC lines with different phenotypes. The result indicated that undifferentiated, but not differentiated type expressed Snail/SIP1. Then, we established transfectants stably expressing Snail and SIP1 in two differentiated cells with E-cad expression. Suppressed expression of E-cad, morphologic change into fibroblastoid feature, and remarkable acceleration of invasion activity were observed in the transfectants. In reverse transcription-polymerase chain reaction series of genes relating to motility and invasion, we demonstrated striking evidence that matrix metalloproteinase (MMP-1), MMP-2, MMP-7, and MT1-MMP expressions were strongly upregulated by Snail. On the other hand, MMP-1, MMP-2, and MT1-MMP expressions were enhanced by SIP1 transfection, however, the intensity was weaker than that in Snail transfection. In conclusion, Snail or SIP1 expression may be induced during HCC progression, where Snail/SIP1 directly represses E-cad gene transcription and activates cancer invasion via the upregulation of the MMP gene family.
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PMID:Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. 1502 11

Tumor hypoxia has been reported to induce tumor progression in several carcinomas. Current studies have shown that hypoxia inducible factor-1alpha (HIF-1alpha) is stabilized under hypoxic conditions and transactivates various genes related to cancer aggressiveness. In the present study, we examined whether hypoxia affects cancer invasion in hepatocellular carcinoma. We aimed to solve the molecular mechanism of tumor invasion under the hypoxic condition. We showed that tumor hypoxia accelerated cancer invasion in two hepatoma cell lines. Using Western blot and RT-PCR analyses we demonstrated striking evidence that the expression of HIF-1alpha, ETS-1, MMP-7 and MT1-MMP was strongly upregulated by hypoxic stimulation. To examine whether these invasion-related genes are regulated by HIF-1alpha, we treated hepatoma cells with TX-402, which was reported to repress HIF-1alpha expression. HIF-1alpha expression was strongly repressed by the TX-402 treatment. In contrast, the expression of ETS-1, MMP-7 and MT1-MMP mRNA was not affected by TX-402 treatment. We further established stable transfectants in which HIF-1alpha dominant negative vector was introduced into Hep3B cells (pHIF-1alphaDN). In the pHIF-1alphaDN cells, the expression of ETS-1, MMP-7 and MT1-MMP was not repressed. Moreover, the invasion activity of pHIF-1alphaDN was not altered, compared with that of the mock. In hepatoma cells, we provided evidence that hypoxic stress accelerates cancer invasion by upregulating ETS-1 and the MMP family by an HIF-1alpha-independent pathway.
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PMID:Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-1alpha-independent manner. 1708 93

The hepatitis B virus (HBV) is a major cause of human hepatocellular carcinoma (HCC) which has a very high mortality rate due to high incidence of metastasis. It is unknown whether HBV contributes to HCC metastasis. In this report, we present clinical data obtained from HCC patients indicating that the expression of hepatitis B virus X protein (HBx) in HCC is associated with an increased expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and matrix metalloproteinase-2(MMP-2), which correlates with a poor prognosis. We further demonstrate experimentally that HBx upregulates MT1-MMP, which in turn induces MMP-2. Significantly, HBx-mediated MMP activation is associated with a marked increase of cell migration, as revealed by both wound-healing and transwell migration assays, suggesting that HBx may facilitate tumor cell invasion by upregulation of MMPs and subsequent destruction of the extracellular matrix. Together, our results support a model in which HBx contributes to HCC metastasis by upregulation of MMPs.
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PMID:The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases. 1718 64

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a versatile proteinase and recent studies indicated it could be internalized. Our earlier study found that it is overexpressed in hepatocellular carcinoma (HCC) and could promote intrahepatic metastasis. The present study was conducted to examine its subcellular localization and its clinicopathological significance in HCC after curative partial hepatectomy. Localization of MT1-MMP in 101 pairs of HCCs and their adjacent liver tissues, and 8 normal liver tissues was examined by the immunohistochemical method. MT1-MMP protein was localized at membrane and cytoplasm of hepatocytes in the normal and tumor adjacent liver tissues. In contrast, the HCCs were highly heterogeneous with variable degrees of membrane, cytoplasmic, and even nuclear staining. Interestingly, patients with presence of nuclear MT1-MMP were associated with poor overall survival (log-rank test, P=0.043) and large tumor size (>5 cm) (Fisher's exact test, P=0.031). Subcellular distribution was further demonstrated by Western blotting and immunofluorescence with Hep3B stable transfectant overexpressing MT1-MMP. Western blot analyses of subcellular fractions confirmed a differential partitioning of various post-translationally modified MT1-MMP in these fractions. Different antibodies corroborated the presence of MT1-MMP in the nuclear fraction. Concomitant nuclear presence of MMP2 with MT1-MMP further indicated its potential involvement in the nuclear functions. MT1-MMP co-localized with caveolin-1 at the perinuclear region, suggesting nuclear translocation of MT1-MMP via caveolae-mediated endocytosis. In summary, the association of nuclear MT1-MMP with aggressive tumor features including poor prognosis and large tumor expands its functional repertoire and further indicates a new functional role of MMPs within nuclei of tumor cells.
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PMID:Atypical localization of membrane type 1-matrix metalloproteinase in the nucleus is associated with aggressive features of hepatocellular carcinoma. 1721 25

Matrix metalloproteinase-11 (MMP-11) belongs to the particular member of MMP family, a group of zinc-dependent endopeptidases involved in tumor progression, invasion and metastasis. MMP-11 is strongly expressed in tumor cells and stromal fibroblasts located in the immediate vicinity of tumor. This study investigated the possible role of MMP-11 expression in mouse hepatocarcinoma cell line Hca-F with highly lymphatic metastasis potential by RNA interference (RNAi) approach. The results showed that a small interfering RNA (siRNA) targeted against MMP-11 significantly impeded Hca-F cells proliferation and colony formation in soft agar, as well as resulted in Hca-F cell apoptosis. This reduction of MMP-11 expression also led to the decreased migration and adhesion of Hca-F cells dramatically both in vitro and in vivo. Furthermore, in vivo metastasis assay indicated that down-regulation of MMP-11 expression in Hca-F cells attenuated the metastatic potential of Hca-F cells to peripheral lymph nodes. These data together provide compelling evidence into the function of MMP-11 and suggest that MMP-11 act as a tumor lymphatic metastasis-associated gene, and could represent a new potential target for gene therapy.
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PMID:siRNA targeted against matrix metalloproteinase 11 inhibits the metastatic capability of murine hepatocarcinoma cell Hca-F to lymph nodes. 1762 64

Previously, we showed that down-regulation of claudin-10 (CLDN-10) in hepatocellular carcinoma is associated with prolonged disease-free survival after curative surgery. Claudins are important tight junction components. Increasing evidence shows that claudins are involved in cancer progression but each member of claudins is specifically expressed in a variety of malignancies. The biological role of CLDN-10 in hepatocellular carcinoma is unexplored. In the current study, we investigated the CLDN-10 function in two different hepatocellular carcinoma cell lines by in vitro assays with the CLDN-10 overexpression and small interfering RNA-mediated knockdown transfectants. We observed that overexpression of CLDN-10 conferred malignant phenotypes to hepatocellular carcinoma cells, Hep3B, which lack CLDN-10 expression, by promoting cancer cell survival, motility, and invasiveness. More importantly, matrix metalloproteinase 2 (MMP2) was up-regulated. Increase in mRNA transcription and protein expression of membrane type 1-MMP (MT1-MMP) was also observed in the CLDN-10 transfectants, where MT1-MMP was a protease shown to promote intrahepatic metastasis in hepatocellular carcinoma in our earlier study. In addition, CLDN-1, CLDN-2, and CLDN-4 was up-regulated in CLDN-10 overexpression transfectants, indicating that the expression of CLDN-10 in cancer cells might affect the expression levels of its family members. On the contrary, small interfering RNA-based knockdown of CLDN-10 in HLE, an invasive cell line with high level of CLDN-10 expression, abolished invasion and strongly decreased activation of MMPs and claudin members expression. These findings showed that CLDN-10 is functionally involved in hepatocellular carcinoma invasion and is a potential target for hepatocellular carcinoma therapy.
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PMID:Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells. 1802 72

Allyl isothiocyanate (AITC) has been reported to exhibit antimetastatic activity, but the mechanism remains unclear. The objective of this study was to determine the effect of AITC on cell adhesion, migration, and metalloproteinase gene expression in SK-Hep1 human hepatoma cells. The gene expression profiles of SK-Hep1 cells were obtained by using the HG-U133A Affymetrix GeneChip human genome array containing 14,500 human genes. Twenty antimetastatic genes including COL4A3, ADAMDEC1, CAPN10, CD14, and ITGB1BP3 were over expressed, while the expression of 35 genes such as COL8A1, MYBPC1, ST14, and SOS2 were down-regulated. Semiquantitative RT-PCR confirmed these results in mRNA levels. Based on these in vitro results, it can be concluded that AITC might be potentially useful in suppressing tumor cell migration and MMP expression.
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PMID:Allyl isothiocyanate influences cell adhesion, migration and metalloproteinase gene expression in SK-Hep1 cells. 1899 1

Streptochlorin is a small molecule isolated from marine Streptomyces sp. that is known to have antiangiogenic and anticancer properties. In this study, we examined the effects of this compound on reactive oxygen species (ROS) production and the association of these effects with apoptotic tumor cell death, using a human hepatocarcinoma Hep3B cell line. The results of this study demonstrated that streptochlorin mediates ROS production, and that this mediation is followed by a decrease in the mitochondrial membrane potential (MMP, m), activation of caspase-3, and downregulation of antiapoptotic Bcl-2 protein. The quenching of ROS generation by N-acetyl-L-cysteine administration, a scavenger of ROS, reversed the streptochlorin-induced apoptosis effects via inhibition of ROS production, MMP collapse, and the subsequent activation of caspase-3. These observations clearly indicate that ROS are involved in the early molecular events in the streptochlorin-induced apoptotic pathway. Taken together, our data imply that streptochlorin-induced ROS is a key mediator of MMP collapse, which leads to the caspase-3 activation, culminating in apoptosis.
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PMID:Streptochlorin isolated from Streptomyces sp. Induces apoptosis in human hepatocarcinoma cells through a reactive oxygen species-mediated mitochondrial pathway. 1904 34

3-(4-(Benzo[d]thiazol-2-yl)-1-phenyl-1H-pyrazol-3-yl) phenyl acetate (DPB-5) is a synthetic benzothiazole derivative. In the present study, we revealed that DPB-5 had strong cytotoxicity to induce cell apoptosis, which was mediated by ROS. And DPB-5 was more cytotoxic toward hepatoma cells than toward normal hepatic cells, which was resulted from the greater susceptibility of the malignant cells to ROS. DBP-5 caused massive ROS accumulation and GSH decrease, which lead to MMP disruption, caspase activation and finally induced cell apoptosis. Additionally, rotenone, an inhibitor of mitochondria electron transport system, effectively blocked the ROS elevated effect of DPB-5, which suggested that DPB-5-induced ROS generated from the mitochondria. Further studies showed that DPB-5-induced cell apoptosis through caspases-cascade, but failed to activate caspase-9. Hence, we concluded that DPB-5-induced Hep G2 cells apoptosis via a ROS-mediated pathway which was caspase-dependent but did not rely on caspase-9.
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PMID:3-(4-(Benzo[d]thiazol-2-yl)-1-phenyl-1H-pyrazol-3-yl) phenyl acetate induced Hep G2 cell apoptosis through a ROS-mediated pathway. 2001 82

Hepatocellular carcinoma (HCC) is an aggressive cancer with a dismal outcome largely due to metastasis and postsurgical recurrence. Thus, the inhibition of invasion and metastasis is of great importance in its therapies. Medicinal plants or ethnopharmacology used in folklore medicine continue to be an important source of discovery and development of novel or potential therapeutic agents for treatment of cancer. Chrysanthemum indicum, one of the medicinal plants or ethnopharmacology, is being used for treatment of many diseases including cancer. However, this plant molecular mechanisms underlining the anti-metastatic effects have not been well documented. In this study, Chrysanthemum indicum ethanolic extract (CIE) significantly suppressed proliferation and invasion of MHCC97H cells, one of the HCC cell lines with high metastatic potential, in a dose-dependent manner. CIE markedly decreased MMP-2 and MMP-9 expression, increased simultaneously TIMP-1, and TIMP-2 expression further restoring their balance in the cancer cells. The present study indicates that CIE reduced MHCC97H cell metastatic capability, in part at least, through decrease of the MMP expression, simultaneous increase of the TIMP expression, further restoring their balance as therapeutic target in HCC. It is suggested that Chrysanthemum indicum is a potential novel therapeutic medicinal plant for treatment of HCC or cancer invasion and metastasis.
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PMID:Chrysanthemum indicum ethanolic extract inhibits invasion of hepatocellular carcinoma via regulation of MMP/TIMP balance as therapeutic target. 2004 2


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