Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic is a known human carcinogen. We have reported that brief exposure of pregnant C3H mice to arsenite in their drinking water during gestation induced hepatocellular carcinoma (HCC) in male offspring after they became adults. Tumor formation is typically associated with multiple gene expression changes, and this study examined aberrant gene expression associated with transplacental arsenic hepatocarcinogenesis. Liver tumors and nontumorous liver samples were taken at necropsy from adult male mice exposed in utero to either 42.5 or 85 ppm arsenic as sodium arsenite or unaltered water from day 8 to 18 of gestation. Total RNA was extracted and subjected to microarray analysis. Among 600 genes, arsenic-induced HCC showed a higher rate of aberrant gene expression (>2-fold and p < 0.05, 14%) than spontaneous tumors (7.8%). Overexpression of alpha-fetoprotein, c-myc, cyclin D1, proliferation-associated protein PAG, and cytokeratin-18 were more dramatic in arsenic-induced HCC than spontaneous tumors. In nontumorous liver samples of arsenic-exposed animals, 60 genes (10%) were differentially expressed, including the increased expression of alpha-fetoprotein, c-myc, insulin-like growth factor binding protein-1, superoxide dismutase, glutathione S-transferases, and CYP2A4, and the depressed expression of CYP7B1. Real-time RT-PCR analysis largely confirmed these findings. This toxicogenomic analysis revealed several aberrant gene expression changes associated with transplacental arsenic carcinogenesis. It is indeed remarkable that expression changes occurred in adulthood even though arsenic exposure ended during gestation. Some of these aberrantly expressed genes could play a role in the development of arsenic-induced tumors, at least in the liver.
 ...
PMID:Toxicogenomic analysis of aberrant gene expression in liver tumors and nontumorous livers of adult mice exposed in utero to inorganic arsenic. 1469 Dec 2

Some hemophilic patients in Japan suffer from infections with both human immunodeficiency virus (HIV) and hepatitis virus because they received contaminated nonheated blood products. Coinfection with HIV appears to accelerate the course of chronic hepatitis. Although powerful antiviral therapy was introduced as HIV treatment and the prognosis of HIV patients was dramatically improved, the risk of rapid progression of hepatitis and carcinogenesis remains for the patients. Recently, we performed surgery for hepatocellular carcinoma (HCC) in two hemophilic patients with HIV and hepatitis C virus (HCV) coinfection. Case 1 was a 52-years-old man who suffered from liver cirrhosis, hypersplenism, and hyperammonemia due to portosystemic shunt. A recent abdominal computed tomography (CT) scan had revealed a low-density area in segment VI of the liver. Splenectomy and partial resection of the liver were performed. Case 2 was a 66-year-old man who had been diagnosed with chronic hepatitis at age 50, and HIV infection at age 52 years. When his serum alpha-fetoprotein level was increased, CT scan of the liver revealed a mass in segment VIII. Subsegmentectmy of the liver was performed. Although the CD4 value in each patient was lower than 200 micro l, the operations were safely carried out and no major complication occurred. Because the chance of encountering HCC patients infected with HIV and HCV is increasing in Japan, we should consider the perioperative care of these patients, as well as the protection of medical workers against HIV infection.
 ...
PMID:Operated hepatocellular carcinoma in two HIV- and HCV-positive hemophilic patients. 1523 96

The aim of our study was assessment of the long-term influence of interferon-alpha (IFN-alpha) treatment on the serum marker of the hepatocarcinogenesis level-alpha-fetoprotein (AFP)-in patients (pts) with chronic viral hepatitis (cvh) B and C. Thirty seven pts (21 with HCV and 16 with HBV infection (20 women, 17 men, aged 24-62) were included in the study. Pts were administered IFN-alpha in the dose of 9-15 MU per week, thrice a week, for 16 weeks (HBV group) or 24-52 weeks (HCV group). Effectiveness of IFN-alpha treatment was evaluated on the basis of the HBV DNA and HCV RNA level in blood. The serum AFP values were determined before and 4-7 years after IFN-alpha treatment. The baseline serum AFP level was increased in 26 out of 37 pts (70%) (14/21 from HCV group; 12/16 from HBV group). After the 4-7 years' follow-up it remained increased only in 2 out of 37 pts (5%). AFP values significantly decreased after IFN-alpha treatment (17.58+/-19.09 IU/ml vs 7.95+/-21.78 IU/ml; p< 0.05; normal range 0-5 IU/ml) in both HBV and HCV, responder and non- responder groups. These results support the hypothesis that IFN-alpha therapy could diminish the risk of liver carcinogenesis in pts with cvh B and C. It significantly decreases the serum AFP level. Its beneficial effect was observed both in responders and in non-responders.
 ...
PMID:Interferon-alfa treatment may reduce the occurrence of liver carcinogenesis in patients with chronic viral hepatitis. 1531 99

The CCAAT/enhancer binding protein alpha (C/EBPalpha) is vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. CEBPA loss-of-function mutations identified in acute myeloid leukemia patients support a tumor suppressor role for C/EBPalpha. Recent work showed reductions of C/EBPalpha levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebpalpha expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebpalpha knock-in mouse in which a single-copy c/ebpalpha is regulated by one allele of the alpha-fetoprotein (AFP) gene promoter. The knock-in mice are physically indistinguishable from wild-type (WT) controls. However, knock-in animals were found to deposit fetal hepatic glycogen earlier than WT animals. Quantitative real-time PCR confirmed early c/ebpalpha expression and early glycogen synthase gene activation in knock-in fetuses. We then used diethylnitrosamine to induce hepatocellular carcinoma in our animals. Diethylnitrosamine produced half the number of hepatocellular nodules in knock-in mice as in WT mice. Immunohistochemistry showed reduced C/EBPalpha content in WT nodules whereas knock-in nodules stained strongly for C/EBPalpha. The p21 protein was examined because it mediates a C/EBPalpha growth arrest pathway. Nuclear p21 was absent in WT nodules whereas cytoplasmic p21 was abundant; knock-in nodules were positive for nuclear p21. Interestingly, only C/EBPalpha-positive nodules were positive for nuclear p21, suggesting that C/EBPalpha may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBPalpha production can inhibit liver tumor growth in vivo.
 ...
PMID:CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma. 1628 22

The Hepatitis B virus X (HBx) protein has been strongly implicated in the carcinogenesis of hepatocellular carcinoma (HCC). However, effects of the HBx protein on cell proliferation and cell death are controversial. This study investigates the effects of the HBx protein on liver regeneration in two independent lines of HBx transgenic mice, which developed HCC at around 14 to 16 months of age. High mortality, lower liver mass restoration, and impaired liver regeneration were found in the HBx transgenic mice post-hepatectomy. The levels of alanine aminotransferase and alpha-fetoprotein detected post-hepatectomy increased significantly in the HBx transgenic livers, indicating that they were more susceptible to damage during the regenerative process. Prolonged activation of the immediate-early genes in the HBx transgenic livers suggested that the HBx protein creates a strong effect by promoting the transition of the quiescent hepatocytes from G0 to G1 phase. However, impaired DNA synthesis and mitosis, as well as inhibited activation of G1, S, and G2/M markers, were detected. These results indicated that HBx protein exerted strong growth arrest on hepatocytes and imbalanced cell-cycle progression resulting in the abnormal cell death; this was accompanied by severe fat accumulation and impaired glycogen storage in the HBx transgenic livers. In conclusion, this study provides the first physiological evidence that HBx protein blocks G1/S transition of the hepatocyte cell-cycle progression and causes both a failure of liver functionality and cell death in the regenerating liver of the HBx transgenic mice.
 ...
PMID:Blocking of G1/S transition and cell death in the regenerating liver of Hepatitis B virus X protein transgenic mice. 1640 55

Chronic arsenic exposure of rat liver epithelial TRL1215 cells induced malignant transformation in a concentration-dependent manner. To further define the molecular events of these arsenic-transformed cells (termed CAsE cells), gene expressions associated with arsenic carcinogenesis or influenced by methylation were examined. Real-time RT-PCR showed that at carcinogenic concentrations (500 nM, and to a less extent 250 nM of arsenite), the expressions of alpha-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), c-jun, c-myc, H-ras, c-met and hepatocyte growth factor, heme oxygenase-1, superoxide dismutase-1, glutathione-S-transferase-pi and metallothionein-1 (MT) were increased between 3 to 12-fold, while expressions of insulin-like growth factor II (IGF-II) and fibroblast growth factor receptor (FGFR1) were essentially abolished. These changes were not significant at the non-carcinogenic concentration (125 nM), except for IGF-II. The positive cell-cycle regulators cyclin D1 and PCNA were overexpressed in CAsE cells, while the negative regulators p21 and p16 were suppressed. Western-blot confirmed increases in AFP, WT-1, cyclin D1 and decreases in p16 and p21 protein in CAsE cells. The CAsE cells over-expressed MT but the demethylating agent 5-aza-deoxycytidine (5-aza-dC, 2.5 microM, 72 h) stimulated further MT expression. 5-Aza-deoxycytidine restored the loss of expression of p21 in CAsE cells to control levels, but did not restore the expression of p16, IGF-II, or FGFR1, indicating the loss of expression of these genes is due to factors other than DNA methylation changes. Overall, an intricate variety of gene expression changes occur in arsenic-induced malignant transformation of liver cells including oncogene activation and alterations in expression of genes critical to growth regulation.
 ...
PMID:Further studies on aberrant gene expression associated with arsenic-induced malignant transformation in rat liver TRL1215 cells. 1687 16

The number of papers published regarding hepatocellular carcinoma increased remarkably over the previous year. The 1-year survival for hepatocellular carcinoma has only improved slightly over the past 20 years, while the overall survival has remained unchanged. Hepatitis B genotypes, specifically genotype B, correlate with better response and survival in patients with hepatocellular carcinoma caused by this chronic infection. A consensus conference recommended that patients with Child-Turcotte-Pugh class A or B cirrhosis should be screened with ultrasound and alpha-fetoprotein measurement every 6 months. Using microarray technology, several groups established the gene expression for human hepatocellular carcinoma including the identification of potential genes involved in hepatic carcinogenesis. Dynamic gadolinium MRI is the preferred imaging of choice for the evaluation of hepatocellular carcinoma, but contrast-enhanced power Doppler ultrasound is a new imaging technique able to differentiate neoplastic from nonneoplastic liver lesions. Overall, transplantation is the best long-term therapeutic option, but in patients without portal hypertension and well-preserved liver function, resection may be preferable.
 ...
PMID:Hepatocellular carcinoma. 1703 5

Glypican-3 (Gpc3), a cell surface-linked heparan sulfate proteoglycan is highly expressed during embryogenesis and is involved in organogenesis. Its exact biological function remains unknown. We have studied the expression of Gpc3 in fetal and adult liver, in liver injury models of activation of liver progenitor cells: D-galactosamine and 2-acetylaminofluorene (2-AAF) administration followed by partial hepatectomy (PH) (2-AAF/PH); and in the Solt-Farber carcinogenic model: by initiation with a single dose of diethylnitrosamine and promotion with 2-AAF followed by PH treatment. Gpc3 expression was studied using complementary DNA microarrays, reverse transcriptase-polymerase chain reaction, in situ hybridization (ISH); ISH combined with immunohistochemistry (IHC) and immunofluorescent microscopy. We found that Gpc3 is highly expressed in fetal hepatoblasts from embryonic days 13 through 16 and its expression gradually decreases towards birth. Dual ISH with Gpc3 and alpha-fetoprotein (AFP) probes confirmed that only hepatoblasts and no other fetal liver cells express Gpc3. At 3 weeks after birth the expression of Gpc3 mRNA and protein was hardly detected in the liver. Gpc3 expression was highly induced in oval cell of D-gal and 2-AAF/PH treated animals. Dual ISH/IHC with Gpc3 riboprobe and cytokeratin-19 (CK-19) antibody revealed that Gpc3 is expressed in activated liver progenitor cells. ISH for Gpc3 and AFP performed on serial liver sections also showed coexpression of the two-oncofetal proteins. FACS isolated oval cells with anti-rat Thy1 revealed expression of Gpc3. Gpc3 expression persists in atypical duct-like structures and liver lesions of animals subjected to the Solt-Farber model of initiation and promotion of liver cancer expressing CK-19. In this work we report for the first time that the oncofetal protein Gpc3 is a marker of hepatic progenitor cells and of early liver lesions. Our findings show further that hepatic progenitor/oval cells are the target for malignant transformation in the Solt-Farber model of hepatic carcinogenesis.
 ...
PMID:The oncofetal protein glypican-3 is a novel marker of hepatic progenitor/oval cells. 1711 58

Recent evidence suggests that some cancers may originate from cancer stem cells, which may derive from carcinogenesis of normal stem cells. A hepatic progenitor cell population, which gives rise to hepatocytes and cholangiocytes, has been suggested in humans, though whether these cells can give rise to malignant tumors has not been confirmed. We report here a case of an alpha-fetoprotein (AFP)-producing intrahepatic cholangiocarcinoma (ICC) in an 81-year-old woman with chronic hepatitis C viral infection, suggesting malignant transformation of hepatic stem cells as a mechanism for hepatic neoplasia. Abdominal computed tomography revealed a low-density mass with surrounding enhancement measuring 5 cm x 5 cm in segments IV and VIII of the liver. The preoperative serum levels of tumor markers were 1.7 ng/ml of carcinoembryonic antigen, 22 mAU/ml of protein induced by vitamin K absence or antagonist II, 43.4 U/ml of carbohydrate antigen 19-9, and 1,560 ng/ml of AFP. Following central bisegmentectomy of the liver, serum AFP levels decreased dramatically. Histologically, the tumor cells showed indistinct glandular structures with abundant fibrous stroma. Immunohistochemical analysis demonstrated that the neoplastic cells reacted strongly to antibodies against AFP and cytokeratin (CK) 7. In addition, cancer cells showed partially positive reaction to anti-CK14, a liver stem cell marker, and to anticluster designation (CD) 133, a hematopoietic stem cell marker, and negative reaction to antihepatocyte paraffin (HepPar) 1. These data may indicate that the tumor was derived from a normal liver stem cell that underwent oncogenic transformation.
 ...
PMID:A case of an alpha-fetoprotein-producing intrahepatic cholangiocarcinoma suggests probable cancer stem cell origin. 1740 96

In this study, we examined the possible involvement of progenitor cells in the carcinogenesis of human hepatocellular carcinoma (HCC) using tissue specimens and cell lines. We used ATP-binding cassette transporter ABCG2 as a progenitor cell marker. Immunohistochemically, ABCG2(+) hepatocytes were observed in the periportal areas of the dysplastic nodule, and ABCG2(+) cancer cells were also scattered or focally clustered in HCC. We sorted the cultured HCC cells (HuH7 and PLC5) into ABCG2(+) and ABCG2(-) subpopulations and then subcultured them for 4 weeks. ABCG2(+) cells could generate ABCG2(+) and ABCG2(-) progenies during subculture, whereas ABCG2(-) cells bore only ABCG2(-) cells, suggesting that a cancer cell hierarchy with reference to ABCG2 exists in HCC cells and that ABCG2(+) cells reside at the higher rank in that hierarchy. Interestingly, other progenitor cell markers including cytokeratin 19 and alpha-fetoprotein were mainly expressed in ABCG2(+) subpopulations. Conversely, albumin expression was more intense in ABCG2(-) cells. In addition, the expression patterns of transcription factors (GATA6, CCAAT/enhancer-binding protein alpha, and CCAAT/enhancer-binding protein beta) in ABCG2(+) and ABCG2(-) cells resembled those during normal liver development. In conclusion, this study suggests that cancer cells with ABCG2 expression might play a central role in hepatocarcinogenesis and the maintenance of the cancer cell hierarchy of human HCC.
 ...
PMID:Histological and culture studies with respect to ABCG2 expression support the existence of a cancer cell hierarchy in human hepatocellular carcinoma. 1745 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>