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)

Patients with advanced hepatocellular carcinoma (HCC) have shown to benefit from tamoxifen treatment. The mechanisms of tamoxifen effects in HCC, however, are not yet clearly understood. The PI3K/Akt/mTOR signal pathway is involved in cell proliferation, tumorigenesis, and apoptosis. Over-expression of survivin has played an important role in leading to antiapoptosis. The current study investigated changes in mTOR pathway and survivin expression in hepatocarcinoma cell line HepG2 treated with tamoxifen. We detected apoptosis of hepatocarcinoma cells by flow cytometry assay. Survivin transcription level and p70S6k was demonstrated by PCR, dual-luciferase reporter assay and western blot analysis respectively. Our results are showed as follows: tamoxifen leads to apoptosis of the cells, and reduction in survivin expression, as well as a dramatic reduction in the activated form of p70S6 kinase. Twenty micromoles tamoxifen treatment significantly depresses transcription of survivin mRNA. Treating HepG2 cells with rapamycin, a specific mTOR inhibitor, significantly reduce survivin protein level but did not affect survivin transcription, which indicated that tamoxifen and rapamycin were synergistic in regards to down-regulation of survivin expression in hepatocellular carcinoma cells. Our results suggest that tamoxifen down-regulate survivin expression in HepG2 cells is mediated by transcriptional and posttranscriptional level via PI3K/Akt/mTOR pathway to induce apoptosis.
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PMID:Involvement of mTOR and survivin inhibition in tamoxifen-induced apoptosis in human hepatoblastoma cell line HepG2. 1993 98

Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of apoptosis and cell proliferation. Overexpression of survivin has been implicated in several human cancers, including human hepatocellular carcinoma (HCC). Although several factors have been shown in vitro to upregulate survivin expression in cancer cells, the in vivo regulators of survivin in human hepato-carcinogenesis are largely unknown. We studied by immunohistochemistry the protein expression of survivin in relation to cyclin D1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), beta-catenin, E-cadherin and phosphorylated-Akt (p-Akt) in 69 cases of HCC and adjacent liver cirrhosis. Survivin was expressed in 63/69 (91.3%) cases of HCC and in 40/47 (85.1%) cases of liver cirrhosis. Survivin localization in HCC was exclusively nuclear, while intense cytoplasmic and low nuclear expression of survivin was observed in cases of cirrhosis. Survivin expression in HCC correlated significantly with low grade tumors, expression of cyclin D1 and p-STAT3. Expression of survivin in liver cirrhosis correlated with downregulation of E-cadherin expression. There was no significant correlation of survivin with beta-catenin or p-Akt in HCC or liver cirrhosis. In conclusion, we showed an association of nuclear survivin with well differentiated HCC, as well as with the expression of the cell cycle regulator cyclin D1. Activation of STAT3 and loss of E-cadherin but not beta-catenin or Akt pathways seem to be implicated in survivin upregulation in HCC and liver cirrhosis.
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PMID:Survivin overexpression in HCC and liver cirrhosis differentially correlates with p-STAT3 and E-cadherin. 2005 2

In order to provide more efficient transduction of plasmid siRNA into target cells, develop more susceptible transduction into cancer cell types, and more easily explore application in animal experiments, we examined development of an adenoviral vector-mediated siRNA expression system and inhibition of survivin gene expression to induce the growth and apoptosis of hepatocarcinoma cells. A system of adenoviral vector-mediated siRNA expression was constructed for the survivin gene. Survivin gene expression in HepG2 cells infected with recombinant adenovirus was detected by Western blot and RT-PCR, and apoptotic cells were investigated by FAC. Western blot analysis showed that the infection of adenovirus-mediated siRNA against survivin efficiently inhibited the expression of survivin in hepatocarcinoma cells with an inhibitory rate of 66.32%. Semi-quantitative RT-PCR showed that survivin gene mRNA transcription was reduced by nearly 72.34% with a peak at 72 h. The number of apoptotic cells increased. In conclusion, results demonstrated that this adenovirus-mediated siRNA system could serve as a useful tool for both basic research on the analysis of gene function and cancer therapy applications.
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PMID:Inhibition of survivin expression to induce the apoptosis of hepatocarcinoma cells by adenovirus-mediated siRNA. 2010 7

In order to research the survivin gene's action on an animal tumor, we used an adenovirus-mediated siRNA system to inhibit the expression of survivin in an animal model of hepatocarcinoma using nude mice. We constructed a hepatocarcinoma model with nude mice using the hepatocarcinoma cell line HepG2 and divided the mice into four groups depending on the injection dose of AdsiRNA-survivin. We injected the constructed survivin-siRNA adenovirus into tumor-bearing nude mice, observed tumor growth, and determined the tumor growth curve. We then detected tumor cell apoptosis using a TUNEL kit that can assay sliced DNA in tumor cells. The growth of tumors injected with a high or low dose of AdsiRNA-survivin was obviously inhibited, and this level of inhibition was positively correlated with the injected dose of adenovirus. Results of the TUNEL test showed that many of the apoptotic cells were brown in color with concentrated nuclei and an irregular cell shape for both the high and low injection doses. The number of apoptotic cells decreased by group in the order of the high dose group, the low dose group, the AdsiRNA-U6 group, and the PBS group. In conclusion, our results demonstrated that an adenovirus-mediated siRNA system can be used for animal experiments in vivo. AdsiRNA-survivin efficiently inhibited tumor growth and induced tumor cell apoptosis, and it did so in a dose-dependent manner.
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PMID:Adenovirus-mediated siRNA inhibited survivin gene expression induces tumor cell apoptosis in nude mice. 2010 33

In this article, we demonstrate that the synthetic cannabinoid R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)-(1-naphthalenyl) methanone mesylate (WIN 55,212-2) sensitizes human hepatocellular carcinoma (HCC) cells to apoptosis mediated by tumor necrosis-related apoptosis inducing ligand (TRAIL). The apoptotic mechanism induced by treatment with WIN/TRAIL combination involved the loss of the mitochondrial transmembrane potential and led to the activation of caspases. In HCC cells, WIN treatment induced the up-regulation of TRAIL death receptor DR5, an effect that seemed to be related to the increase in the level of p8 and CHOP, two factors implicated in cellular stress response and apoptosis. This relationship was suggested by the observation that the down-regulation of p8 or CHOP by specific small interfering RNAs attenuated both WIN-mediated DR5 up-regulation and the cytotoxicity induced by WIN/TRAIL cotreatment. Moreover, WIN induced a significant decrease in the levels of some survival factors (survivin, c-inhibitor of apoptosis protein 2, and Bcl-2) and in particular in that of the active phosphorylated form of AKT. This event seemed to be dependent on the transcription factor peroxisome proliferator-activated receptor-gamma whose level significantly increased after WIN treatment. Therefore, both the induction of DR5 via p8 and CHOP and the down-regulation of survival factors seem to be crucial for the marked synergistic effects induced by the two drugs in HCC cells. Taken together, the results reported in this article indicate that WIN/TRAIL combination could represent a novel important tool for the treatment of HCC.
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PMID:The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating p8/CCAAT/enhancer binding protein homologous protein (CHOP)/death receptor 5 (DR5) axis. 2015 39

The activation of signal transducer and activator of transcription 3 (STAT3) has been linked with the proliferation, survival, invasion, and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Agents that can suppress STAT3 activation have potential for the prevention and treatment of HCC. In this study, we tested an agent, beta-escin, for its ability to suppress STAT3 activation. We found that beta-escin, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed the beta-escin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that beta-escin induced the expression of tyrosine phosphatase Src homology phosphatase 1 that correlated with the down-regulation of constitutive STAT3 activation. beta-Escin also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally, beta-escin inhibited proliferation and also substantially potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, these results suggest that beta-escin is a novel blocker of STAT3 activation that may have potential in the suppression of proliferation and chemosensitization in HCC.
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PMID:Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. 2037 17

Caspase 8 and survivin are known as key molecules of apoptosis in hepatocellular carcinoma (HCC). The purpose of the present study was to investigate the relationship between promoter methylation and expression and apoptotic function of caspase 8 and survivin in HCC. Promoter methylation of the caspase 8 and survivin gene was analyzed in 73 primary HCC using methylation-specific polymerase chain reaction. The relationship between immunohistochemical expression of gene products and proliferative/apoptotic indices, and clinicopathological parameters was also investigated. Twenty-five (34%) and 24 (33%) patients had promoter methylation of caspase 8 and survivin gene. Immunohistochemical staining of caspase 8 and survivin was observed in 35 (48%) and 32 (44%). The methylation of caspase 8 and survivin demonstrated a negative correlation with immunohistochemical expression of gene products (P= 0.049 and P= 0.001). Methylation of caspase 8 and positive expression of its gene product was significantly correlated with high apoptotic indices (P= 0.032 and P= 0.026). Nuclear survivin expression was significantly correlated with high proliferative index (P= 0.001). On survival analysis, positive nuclear survivin expression was associated with a poor prognosis in HCC (P= 0.043). In conclusion, epigenetic alteration by promoter methylation of caspase 8 and survivin may constitute an important regulatory mechanism for expression of those genes in HCC.
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PMID:Epigenetic methylation and expression of caspase 8 and survivin in hepatocellular carcinoma. 2040 46

The fibrolamellar variant of hepatocellular carcinoma (FLC) differs from conventional hepatocellular carcinoma (HCC) in some clinical and pathological features. The authors investigated possible differences in reactivity between FLCs and HCCs using glypican-3 (GPC3), an oncofetal protein, and survivin, an antiapoptotic protein. They also compared staining of FLC and HCC with antibodies to cytokeratins 7 (CK7) and 19 (CK19) and CD34. GPC3 was significantly more often and more strongly expressed in HCCs (72%) than in FLCs (17%). Survivin nuclear translocation in tumor cells did not differ between HCCs (10%) and FLCs (9%). There was more abundant expression of CK7 in FLCs (92%) than in HCCs (33%), whereas CK19 was more often found in HCCs (20%) than in FLCs (5%). All tumors had CD34-positive sinusoids. This study shows that FLCs and HCCs differ in the expression of GPC3, CK7, and CK19 and that there is a lack of difference as regards survivin and CD34.
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PMID:Fibrolamellar hepatocellular carcinoma: an immunohistochemical comparison with conventional hepatocellular carcinoma. 2044 31

Hepatocellular carcinoma (HCC) is known to be resistant to chemotherapy. Survivin, a member of the inhibitor of apoptosis proteins, is overexpressed in most cancers but is absent in most normal adult tissue. The aim of this study was to investigate whether expression of survivin contributes to resistance to cisplatin-induced apoptosis. We confirmed induction of survivin expression in hepatoma in the N-diethylnitrosamine (DEN) induced rat and in the rat hepatoma cell line (K-251). We examined cell proliferation after treatment with cisplatin (CDDP) in the presence and absence of siRNA or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 to suppress survivin or PI3K/Akt, respectively. Survivin was expressed in DEN-induced rat HCC with RT-PCR and Western blotting. Expression of survivin was observed primary in the nuclei and in the cytoplasm with immunohistochemistry. However, survivin was not detected in non-tumor tissues. Expression of survivin was also observed primarily in the nuclei and in the cytoplasm of the K-251 rat hepatoma cell line. CDDP induced survivin expression, which was blocked by siRNA. LY294002 also attenuated survivin expression induced by CDDP. Our results indicate that survivin expression via PI3K contributes to resistance to CDDP-induced apoptosis in a rat hepatoma cell line.
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PMID:Resistance to cisplatin-induced apoptosis via PI3K-dependent survivin expression in a rat hepatoma cell line. 2051

Hepatocellular carcinoma (HCC) is a tumor with rather bad prognosis. Recent years, however, have seen considerable progress in the diagnostics and treatment of this disease, contributing to better understanding of its molecular pathogenesis. Large regenerative nodules, low and high grade dysplastic nodules are premalignant alterations of HCC developing on the grounds of cirrhosis. Microscopically the WHO distinguishes trabecular, acinar (pseudoglandular), scirrhous and solid forms. Special histological subtypes are the clear cell, fibrolamellar and mixed hepato-cholangiocellular variants. The prognostic significance of these histological types is argued. The fibrolamellar, non-cirrhotic form of HCC occurring in young age is considered to be of better prognosis, but this is probably due to the fact that this type is not accompanied by cirrhosis. Certain tumor markers may help the diagnosis, such as alpha-fetoprotein (AFP), glypican-3, survivin, the recently described agrin and claudins, furthermore, the hepatocyte specific antigen (HSA), which confirms the hepatocytic origin of the tumor. Recently, the diagnostic significance of microRNAs, primarily of the hepatocyte-specific mir122 has also emerged. In addition to the Barcelona Clinic Liver Cancer (BCLC) staging classification which determines the course of therapy, the molecular classification of HCC is based on key molecular alterations, many of which are observable in all HCC cases, whereas some alterations are only detectable in certain tumors.
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PMID:[Hepatocellular carcinoma--from macroscopy to molecular pathology]. 2051 81


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