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

The clinical impact of survivin on human cancer pathogenesis and prognosis has been investigated. To clarify the clinical effect of survivin on tumor behavior and prognosis of patients with hepatocellular carcinoma (HCC), the expression of survivin mRNA in 40 samples of HCC tissue and matched-adjacent liver tissue, as well as 7 healthy hepatic tissue samples were measured by a real-time reverse transcription polymerase chain reaction. The expressed level of survivin mRNA (log copies/microg total RNA) in healthy liver tissue was 1.95+/-0.44, in morbid liver tissue adjacent to the tumors was 4.79+/-0.96, and in HCC tissue was 5.87+/-0.73 (values are mean +/- SD and P<0.001). The amount of survivin mRNA in HCC tissues correlated negatively with the apoptotic indices (r=-0.573 and P<0.001) and correlated positively with the proliferation indices (r=0.433 and P=0.005). Expression of survivin was significantly related with histologic grade (P=0.011) and pathological tumor stage (P=0.017). Patients with HCC tumors that had a large amount of survivin mRNA (> or = mean) had lower survival rate (P=0.030), but multivariate analysis showed only Ki-67 labeling index, histologic grade, and pathologic T stage to be the independent prognosticators. These findings indicate that survivin is associated with reduced tumor cell apoptosis, increased tumor cell proliferation, and histologically aggressive tumor features, and may play an important role in tumor progression of HCC. However, further examination is needed to clarify its predictive significance for HCC patients.
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PMID:Expression of survivin mRNA associates with apoptosis, proliferation and histologically aggressive features in hepatocellular carcinoma. 1554 36

IAPs (inhibitors of apoptosis proteins) might have a major role in the apoptotic resistance that marks many cancers. The studies on IAPs in human HCC have focused on survivin or XIAP, indicating that their new or increased expression in this tumor is associated with a more unfavorable prognosis. The present results corroborate these findings, emphasizing the role that the coordinated expression of different IAPs and alternative splice variants might play in the adverse biology of hepatocellular carcinoma.
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PMID:Expression of IAPs and alternative splice variants in hepatocellular carcinoma tissues and cells. 1565 Feb 54

To study the influence of siRNA targeting survivin gene on the biological behavior of hepatocellular carcinoma (HCC), one pair of 21bp reverse repeated. motifs of survivin target sequence with 9 spacers were synthesized and inserted into plasmid psilencer2. 1 to generate siRNA eukaryotic expression vector. After stable transfection into HepG2 cells, the biological behaviors of the survivin siRNA transfected HCC cells were observed. After the recombinant plasmid Psilence (+)-survivin was successfully constructed, survivin mRNA and protein expression inhibition ratio reached 73 % and 75% respectively compared to control groups. Transfected cells with survivin siRNA demonstrated significantly inhibited cell growth and increased apoptosis. Subsequent study in nude mouse model demonstrated lower succeeding rate in cells transfected with survivin siRNA and slow growth rate. The results elucidated the siRNA targeting survivin gene could specially suppress its expression in HepG2 cells and inhibit tumor cells growth both in vivo and in vitro. This provides a theoretical basis to turn the drug resistance in tumor cells.
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PMID:Effect of siRNA targeting survivin gene on the biological behavior of hepatocellular carcinoma. 1593 7

The serious result of hepatitis B (HBV) virus infection is development of hepatocellular carcinoma (HCC). However, the reason of development of HCC in HBV infected patients is still unclear. Recently, the suppression of cell apoptosis is found to relate with the development of cell carcinogenesis, therefore, the expression of apoptosis inhibitor in the virus related cancer line such as hepatoma cell line HepG2.215 was investigated. There are at least six Human apoptosis inhibitors (IAP) have been identified now. They are cIAP1, cIAP2, XIAP, NAPI, survivin and pIAP. Using gene-assay technology, we have recently compared the expression of IAPs in the HepG2.215 cells that persistently expresses Hepatitis B virus by integrated HBV genome with its parent cell line HepG2. The results suggest that there was obviously increase of cIAP2 and cIAP1 in the HepG2.215 cells versus HepG2 cells. Those observations imply a possibility of long time HBV infection could induce the over-expressing apoptosis inhibitors, furthermore, causing the liver cancer. The high expression of cIAP1 and cIAP2 in HBV expressing cells was confirmed by RT-PCR and Northern blot analysis. However, we did not find the change of NIAP and suvivin in HepG2.215 cells. In contrast, the expression of XIAP was down in the HepG2.215 cells comparing with HepG2 cells. How HBV triggers the over-expression of apoptosis inhibitor is unclear. Transient transfection of HepG2 cells with the plasmids expressing different HBV proteins such as S, M, L, X and core proteins did not give a decisive conclusion. Further study is going on now.
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PMID:High level expression of apoptosis inhibitor in hepatoma cell line expressing Hepatitis B virus. 1596 37

Two hepatoma cell lines were incubated for 72 h with ATRA and its analog 13cisRA and according to MTT assay, Hep3B cells were highly susceptible whereas HepG2 cells were more resistant to the treatment. At the high concentration of 166 microM, retinoids were able to induce apoptosis in both cell lines and the highest effect was observed in HepG2 cells treated with ATRA. TUNEL-based photometric ELISA showed that at the same retinoid concentration tested by flow cytometry, both cell lines showed apoptosis whereas plasma membranes were not significantly disrupted. Inhibitors of apoptosis Bcl-xL and survivin were downregulated in Hep3B cells by treatment with both retinoids. Bax, a pro-apoptotic protein, was not significantly upregulated in Hep3B cells, but was slightly increased in HepG2 cells treated with 13cisRA. Both procaspase-3 and procaspase-8 were cleaved in Hep3B cells, suggesting apoptosis could be triggered through the extrinsic pathway. In the case of HepG2 cells, lack of caspase activation suggests a mechanism dependent on other kind of proteases.
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PMID:Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2. 1613

Autoantibodies against tumor-associated antigens (TAAs) such as insulin-like growth factor II mRNA-binding proteins (IMPs), p53, c-myc, and survivin were analyzed in patients with hepatocellular carcinoma (HCC), using recombinant proteins of these antigens. Eight of 86 (9.3%) HCC patients had one or more of these autoantibodies. However, serum alpha-fetoprotein (AFP) levels ranged within normal limits in HCC patients with anti-TAAs except for one case with anti-IMP1. One of the HCC patients had autoantibodies against IMP1, IMP3 and p53 before the diagnosis of HCC. These findings may indicate that anti-TAAs seem to be supplementary serological markers for the diagnosis of HCC in AFP-negative cases and that autoantibodies against IMP1, IMP3 and p53 are candidates for predictive markers of HCC development.
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PMID:Analyses of autoantibodies against tumor-associated antigens in patients with hepatocellular carcinoma. 1614 26

The hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). The relationship was examined between HBV antigens and IAP (inhibitor of apoptosis) family in development of HCC. The expression levels of HBV antigens (HBsAg, HBcAg, and HBxAg) and members of the IAP family (survivin, XIAP, cIAP-1, and cIAP-2) were detected immunohistochemically in tissues from 34 cases of HCC and 30 cases of liver cirrhosis. The positive rate of survivin was higher than these three molecules in all three tissue types (P < 0.05). The positive rates of HBxAg and survivin were high in HCC (76.5% and 88.2%), paratumor (85.3% and 91.2%), and liver cirrhosis (100% and 93.3%) tissues, with no significant differences between the survivin- and HBxAg-positive rates (each P > 0.05). To examine the effect of HBx on survivin expression, plasmid pCMV-X (encoding the HBx gene) was transfected transiently with or without plasmid pcDNA3-sur (encoding the survivin gene) into H7402 hepatoma cells and L-O2 human normal liver cells. Cells over-expressing HBx alone showed increased apoptosis along with a dose-dependent increase in survivin levels. However, co-expression of survivin inhibited the HBx-induced apoptosis. To examine the effect of HBx on survivin in hepatoma cells without apoptosis, plasmid pCMV-X was transfected stably into human hepatoma H7402 cells and L-O2 cells. These H7402-X and L-O2-X cells showed high-level expression of both HBx and survivin, but did not show apoptosis. The addition of pSilencer 3.0-X, an RNAi vector targeting the HBx gene, reduced the expression levels of survivin protein in H7402-X cells. Collectively, these data demonstrate that HBx upregulates survivin expression in hepatoma tissues, suggesting that HBx and survivin may both be involved in carcinogenesis of HCC.
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PMID:Hepatitis B virus X protein upregulates survivin expression in hepatoma tissues. 1617 17

The inhibitors of apoptosis (IAPs) family regulate apoptosis by preventing the action of the central execution phase, and function as mediators and regulators of the anti-apoptotic activity of the v-Rel and NF-kappaB transcription factor families. The targeting of IAPs may be a promising strategy, but it is not well elucidated in human hepatocellular carcinomas (HCCs). We have therefore investigated the effects of the down-regulation of IAPs (XIAP or survivin) on the TNF-related apoptosis-inducing ligand (TRAIL) and chemotherapeutic agents that induced apoptosis in human HCC cells. To inhibit the IAPs gene expression, we designed small interfering RNA (siRNA) against the X-chromosome-linked IAP (XIAP) or survivin and investigated their efficacy in the suppression of the XIAP or survivin expression in two HCC cells (SK-Hep1 and HLE), and their consequent antitumor potential. We found that the designed siRNAs against the XIAP and survivin downregulated the protein expression of respective genes by almost 50%. The suppression of IAPs resulted in a significant decrease in procaspase-3 levels, especially by suppression of the XIAP. The apoptosis cell count was small in cells transfected with control siRNA and siRNA against the XIAP or survivin, but after treatment with 10 ng/ml of TRAIL, the apoptosis cells increased 2-3 times by the suppression of IAPs as control. The cytotoxicity of doxorubicin and camptothecin was augmented by the suppression of the XIAP in SK-Hep1 cells, whereas the suppression of survivin did not affect cytotoxicity. In conclusion, downregulation of the XIAP or survivin enhances cell death by TRAIL and increases sensitivity against some chemotherapeutic agents in HCC cells. In particular, the XIAP may be a potential target to increase therapeutic sensitivity.
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PMID:Targeting of X-linked inhibitor of apoptosis protein or survivin by short interfering RNAs sensitize hepatoma cells to TNF-related apoptosis-inducing ligand- and chemotherapeutic agent-induced cell death. 1621 2

The question that transforming growth factor-beta (TGF-beta) provides a tumor-suppressive or a tumor promoting role is still unknown in hepatocellular carcinoma (HCC). In the present study, we quantitatively investigated the gene expression levels of TGF-beta in liver tissues from patients with HCC. We also evaluated the prognostic importance of TGF-beta gene in HCC patients. A total of 59 patients with primary HCC who underwent hepatectomy between 1993 and 2001 were enrolled. TGF-beta gene expression levels of tumors and of noncancerous livers were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The percentage of apoptotic cells in tumor cells (apoptotic index: AI) was evaluated with immunohistochemistry. Also the expression of survivin protein (apoptosis inhibitor) in tumors was detected by immunohistochemistry. TGF-beta gene expression levels of tumors were compared with clinicopathological findings of patients. The relative expression level of TGF-beta mRNA of 59 tumor tissues did not differ from those of 8 normal liver tissues or 59 noncancerous liver tissues. The mean AI of 29 tumors with normal expression levels of TGF-beta gene (4%) was significantly higher than that of 30 tumors with low expression levels of TGF-beta gene (2.5%, p = 0.03). Thirteen out of 30 tumors (43%) with low expression level of TGF-P gene showed survivin positive, while only 4 out of 29 tumors (14%) with preserved expression of TGF-beta gene showed survivin positive. This difference was significant (p = 0.012). The overall 5-year survival rate of 29 patients with tumors with preserved TGF-beta gene prolonged to 72% compared with that of 30 patients who had tumors with suppressed TGF-beta gene (58%, p = 0.156). In HCC, TGF-beta gene may play a defensive role against tumor progression by regulating survivin protein expression and by controlling occurrence of spontaneous apoptosis in tumors.
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PMID:The gene expression level of transforming growth factor-beta (TGF-beta) as a biological prognostic marker of hepatocellular carcinoma. 1627 May 28

Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2 in the development and progression of various human cancers. Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we have recently observed that the dual COX-1/COX-2 inhibitor indomethacin induces apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively than the selective COX-2 inhibitors, possibly implicating COX-1 in HCC. In this study we investigated the expression of COX-1 in non-tumor and malignant human liver tissues, as well as the effects of the highly selective COX-1 inhibitor SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1 was detected in nearly all the samples assayed, although with a high variability between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive cells was significantly higher in the NT tissues than in the tumors (p<0.0001). In well-differentiated HCC COX-1 expression was significantly higher than in the poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent inhibitory effect on HCC cell growth. The combination of the COX-1 inhibitor with nimesulide and CAY10404, two selective COX-2 inhibitors, resulted in additive effects on cell growth inhibition. SC-560 also inhibited colony formation in soft agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover, SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion, we report for the first time that the selective COX-1 inhibitor SC-560 exhibits anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and present results suggest that both COX-1 and COX-2 inhibitors may have potential therapeutic implications in HCC patients.
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PMID:The selective cyclooxygenase-1 inhibitor SC-560 suppresses cell proliferation and induces apoptosis in human hepatocellular carcinoma cells. 1639 22


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