UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibodies were raised against seven major matrix metalloproteinases: stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), interstitial collagenase (MMP-1), M(r) 72,000 type IV collagenase (72 kDa type IV collagenase, MMP-2), M(r) 92,000 type IV collagenase (92 kDa type IV collagenase, MMP-9) and matrilysin (PUMP, MMP-7) as well as against prolyl 4-hydroxylase, to study the expression of these collagenolytic enzymes in normal liver in relation to the activity of collagen synthesis. Tissue samples of four normal human livers, three hepatocellular carcinomas and one cholangiocellular carcinoma were analysed. In normal liver we found expression of stromelysin-1, stromelysin-3, interstitial collagenase, M(r) 72,000 and M(r) 92,000 type IV collagenases and varying expression of prolyl 4-hydroxylase. Stromelysin-2 was inconsistently detectable; matrilysin was not found. In hepatocellular carcinoma the expression pattern of matrix metalloproteinases showed only minor changes compared with the normal tissue; stronger signals than in normal tissue were seen for stromelysin-1, and stromelysin-2 was also strongly positive. M(r) 72,000 and M(r) 92,000 type IV collagenases and interstitial collagenase were less strongly expressed; stromelysin-3 was unchanged. Expression of prolyl 4-hydroxylase was also increased compared with normal liver. Matrilysin was only seen in cholangiocellular carcinoma, which showed a completely different pattern of matrix metalloproteinase expression. Our results show that metalloproteinases are expressed in human liver with much greater abundance than previously described. Their expression pattern is not changed fundamentally in hepatocellular carcinoma but is completely different from that of other tumour tissues such as cholangiocellular carcinoma.
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PMID:Expression pattern of matrix metalloproteinases in human liver. 763 22

Although matrix metalloproteinases (MMPs) are thought to be involved in the invasion and metastasis of a variety of malignant tumors, including human hepatocellular carcinoma (HCC), the mechanisms for the expression of MMPs in HCC are not known. To understand the mechanism(s) of MMP expression, the expression of matrilysin (MMP-7) and several genes of the Ets transcription factor family was investigated in human HCC and hepatoma-derived cell lines. The role of Ets-1 gene expression in HCC was also studied. Analysis by semiquantitative reverse transcription-PCR revealed that MMP-7 and Ets-1 are overexpressed and closely associated in HCC. To clarify the role of Ets-1, hepatoma cells were transduced with human Ets-1 or targeted with the Ets-1-specific antisense oligonucleotides. Cells stably transduced with the Ets-1 gene showed increased MMP-7 expression compared to parental and mock-transfected cells. Cells targeted with Ets-1-specific antisense oligonucleotides showed reduced expression of MMP-7. Cotransfection of cells with a MMP-7 promoter-reporter gene plasmid and an Ets-1 expression vector yielded an increase in MMP-7 promoter activity in an Ets-1-responsive element-dependent manner. Taken together, these data suggested that the Ets-1 oncogene is up-regulated and involved in the overexpression of MMP-7 in human HCC and may contribute to the progression of HCC.
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PMID:Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. 1110 22

Beta-catenin integrates intracellular WNT signalling and the intercellular E-cadherin-catenin adhesion system. To date, little is known about the role of beta-catenin activation and nuclear accumulation in hepatocarcinogenesis. This study has analysed beta-catenin expression patterns in human dysplastic nodules (DNs), as well as in hepatocellular carcinomas (HCCs) in comparison with proliferation, expression of WNT-1 target genes, E-cadherin, and p53. One hundred and seventy HCCs and 25 DNs were categorized according to established criteria and analysed for the expression pattern of beta-catenin. Analysis of the proliferative activity and expression of E-cadherin, cyclin D1, MMP-7, c-myc, and p53 was performed on a representative subgroup of cases. All DNs lacked nuclear beta-catenin, while 36% of all HCCs were positive, with the number of nuclear stained cells ranging from less than 1% to more than 90%. Increasing nuclear accumulation of beta-catenin correlated with reduced membranous E-cadherin expression and nuclear p53 but not with proliferation. Cyclin D1, MMP-7, and c-myc expression was detected in 54%, 26%, and 65% of HCCs, respectively, but did not correlate with nuclear beta-catenin, proliferation, or grading. Sequence analysis of the beta-catenin gene revealed no detectable mutations in DNs, but mutations in the GSK-3beta binding site were present in 14.3% of the HCCs. In conclusion, this study has demonstrated that nuclear accumulation of beta-catenin is a frequent progression event in human hepatocarcinogenesis which correlates with nuclear p53 accumulation and loss of membranous E-cadherin, but not with the expression pattern of established WNT-1 target genes. It is hypothesized that the role of beta-catenin in human HCC differs significantly from its established function in colon carcinogenesis.
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PMID:Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. 1451 42

Matrix metalloproteinases (MMPs) specially degrade extracellular matrix (ECM) proteins and are involved in tissue remodeling and angiogenesis. Therefore, studies on the role of MMPs in the carcinogenesis, proliferation and infiltration of hepatocellular carcinoma (HCC) may greatly contribute to the development of a new clinically applicable therapeutic approach. In the present study, we immunologically examined the expression rates of various MMPs including MMP-2, 3, 7, 9, membrane type 1-MMP (MT1-MMP), and MT2-MMP in the cancerous and noncancerous areas of resected tumor specimens from 30 patients with primary HCC. The rate of MMP-2 expression was high for both cancerous and noncancerous areas. However, the expression rates of MMP-3, MT1-MMP, and MT2-MMP were significantly higher in cancerous areas than in noncancerous areas. Next, we examined the clinicopathologic features such as the number of tumor nodules, maximal tumor size, presence or absence of capsular infiltration and portal vein invasion, histological grades of HCCs, state of noncancerous areas (chronic hepatitis: CH or liver cirrhosis: LC), and short-term recurrence after resection (within six months). In conclusion, it was found that three main networks of MMPs are predominantly involved in the case of HCC, that is, MMP-2 and MT1-MMP in the carcinogenesis and progression, MMP-7 and MMP-9 in the capsular infiltration and portal vein invasion, as well as MMP-3 and MMP-7 in the progression of HCC. Furthermore, MT1-MMP appeared to be the most important factor in HCC because of its widespread pattern of expression.
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PMID:A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma. 1458 7

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

Matrix metalloproteinases (MMPs) relate to the growth and infiltration of cancer cells, but the frequency and amount of their expression are not yet fully examined in hepatocellular carcinoma. Expression of MMPs (MMP-2, MMP-7, MMP-9, MT1-MMP, MT2-MMP, MT3-MMP) and tissue inhibitors of metalloproteinase (TIMP: TIMP-1, TIMP-2) was investigated on cultured hepatocellular carcinoma (HCC) cells and surgically resected HCC tissues. The cultured cells and tissues expressed MMPs and TIMPs at various degrees, and high expression was observed for MMP-2, MMP-9, MT1-MMP and TIMP-2. Expression of MMP-7, MT2-MMP and TIMP-1 was found at a low frequency and a low amount in both the cells and the tissues. MMP-2 was expressed in various cells: HCC cells, vascular wall and sinusoidal endothelial cells in the cancer area of surgically resected tissues; and hepatocytes, bile duct cells, vascular wall, macrophages and Kupffer cells in the non-cancerous area. MMPs and TIMPs were expressed at a relatively high frequency in hepatocytes of the cancerous area and surrounding non-cancerous area as well as in the other cells and tissues. MMPs and TIMPs may be involved in the progression of hepatocellular carcinoma including the infiltration of cancer cells.
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PMID:Expression of matrix metalloproteinases (MMPs) in cultured hepatocellular carcinoma (HCC) cells and surgically resected HCC tissues. 1587 Sep 19

Molecular markers can provide additional information to traditional histomorphological evaluation for the assessment of tumor progression and predicting the likelihood of invasion and metastasis in various types of malignancies. We studied the association of E-cadherin, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinase with the progression and metastasis of hepatocellular carcinoma. Tissue microarray including six normal livers, 14 cirrhotic livers, 39 macroregenerative nodules, 16 dysplastic nodules, 22 grade I hepatocellular carcinomas, 43 grade II hepatocellular carcinomas, seven grade III hepatocellular carcinomas, and 10 metastatic hepatocellular carcinomas were stained immunohistochemically with antibodies against MMPs -1, -2, -3, -7, -9, tissue inhibitors of metalloproteinase-1, -2, -3, and E-cadherin. The intensities of staining were scored manually by two pathologists and verified by the Chromavision Automated Cellular Imaging System. Compared with normal liver, cirrhotic liver had significantly lower E-cadherin and tissue inhibitors of metalloproteinase-1 but higher MMP-1 and -7, which suggest a more favorable environment for tumor invasion and metastasis. Grade I and grade II hepatocellular carcinomas demonstrated high E-cadherin and decreased MMP-3 and -9, which may explain the rarity of extrahepatic metastasis in low-grade hepatocellular carcinomas despite the high circulatory volume of the liver. The histological progression from dysplastic nodule to well-differentiated hepatocellular carcinoma and to less differentiated tumors was associated with a gradual decrease in tissue expression of E-cadherin, tissue inhibitors of metalloproteinase-2 and -3. Metastatic hepatocellular carcinomas showed significantly lower level of tissue inhibitors of metalloproteinase-1, -2, -3 but higher level of MMP-7. These data suggest that tissue expression of E-cadherin, certain MMPs, and tissue inhibitors of metalloproteinases could be useful markers to predict the progression and metastasis of hepatocellular carcinoma.
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PMID:Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma. 1647 79

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

Matrix metalloproteinases (MMPs) have been implicated in the tumor invasion and growth through the degradation of extracellular matrix. In this study, we selected 46 hepatocellular carcinoma (HCC) cases, at random, and we immunohistologically examined the expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, in cancerous and non-cancerous areas using avidin-biotin-peroxidase complex method. In all cases, cancer cells, hepatocytes, sinusoidal lining cells, leukocytes, and bile ducts were positive for all the primary antibodies. The expressions of MMPs and TIMPs in most of the HCC tissues were equal or low compared with those in the surrounding non-tumor tissues, although mixed expression pattern were recognized in some HCC tissues. The difference of MMP and TIMP expression was not related with the histological differentiation of HCC and the condition of non-cancerous area. These findings suggested little association of the clinicopathological findings of HCC with the histological expression of MMPs and TIMPs.
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PMID:Expression of matrix metalloproiteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in hepatocellular carcinoma tissue, compared with the surrounding non-tumor tissue. 1756 13

Previous studies have suggested that the functional polymorphisms in the promoters of matrix metalloproteinases (MMP) genes were associated with the risk of cancers, but no study has ever explored these polymorphisms as risk factors for hepatocellular carcinoma. Recently, we firstly examined whether seven functional polymorphisms in the promoters of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, and MMP-13 have any bearing on the risk of hepatocellular carcinoma, but we found none. In this study, we focused on an additional six MMP polymorphisms, including four functional polymorphisms in the promoters of MMP-7 (A-181G and C-153T) and MMP-8 (C-799T and A-381G), and two nonsynonymous polymorphisms in MMP-10 (A180G) and MMP-21 (C572T). With the polymorphism validation, we found that only MMP-7 A-181G, MMP-8 C-799T, and MMP-21 C572T were polymorphic. These three polymorphisms were then genotyped in 434 patients with hepatocellular carcinoma and 480 controls by PRC-RFLP analysis. The associations between the polymorphisms and hepatocellular carcinoma risk were evaluated while controlling for confounding factors. No significant association with the risk of hepatocellular carcinoma was observed with the three polymorphisms in the overall sample, hepatitis B virus carriers, and non-hepatitis B virus carriers after correction for multiple comparisons. Furthermore, when the analyses were stratified by age, sex, status of smoking and drinking, pack-years of smoking, and family history of hepatocellular carcinoma, there was also no significant association between these polymorphisms and hepatocellular carcinoma risk. Our findings suggest that the polymorphisms MMP-7 A-181G, MMP-8 C-799T, and MMP-21 C572T may not play a major role in mediating susceptibility to hepatocellular carcinoma.
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PMID:No association of MMP-7, MMP-8, and MMP-21 polymorphisms with the risk of hepatocellular carcinoma in a Chinese population. 1876 25

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