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)

Active telomerase is present in the majority of malignant human tumors, including most cases of hepatocellular carcinoma (HCC). Telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, has been found to be expressed in HCCs, dysplastic (precancerous) nodules (DNs), and regenerative nodules arising in cirrhosis. In a study reported in this issue of the journal, hTERT mRNA levels were assessed by quantitative real-time RT-PCR in various nodular lesions dissected from liver specimens of patients with chronic hepatitis B. High levels of hTERT mRNA were present in HCCs, high-grade DNs, and occasional low-grade DNs, whereas low levels were found in normal livers, livers with chronic hepatitis B (with or without cirrhosis), large regenerative nodules, and most low-grade DNs. Therefore, quantitative assessment of hTERT mRNA may provide a useful adjunct to histopathologic evaluation of large hepatic nodules. Indeed, emerging data from gene expression analyses of DNs and HCCs suggest that hTERT can be included in sets of select genes that provide "molecular signatures" with utility in the diagnosis and management of nodular hepatic lesions. Most importantly, tackling the mechanisms of telomerase activation may provide new means of therapy for HCC and other cancers.
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PMID:Telomerase activation in human hepatocarcinogenesis. 1649 81

Human telomerase reverse transcriptase, hTERT, has been identified as the catalytic enzyme required for telomere elongation. hTERT is expressed in most tumor cells but seldom expressed in most human adult cells. It has been reported that 80% to 90% of hepatocellular carcinomas (HCCs) express hTERT, making the enzyme a potential target in immunotherapy for HCC. In the current study, we identified hTERT-derived, HLA-A*2402-restricted cytotoxic T cell (CTL) epitopes and analyzed hTERT-specific CTL responses in patients with HCC. Peptides containing the epitopes showed high affinity to bind HLA-A*2402 in a major histocompatibility complex binding assay and were able to induce hTERT-specific CTLs in both hTERT cDNA-immunized HLA-A*2402/Kb transgenic mice and patients with HCC. The CTLs were able to kill hepatoma cell lines depending on hTERT expression levels in an HLA-A*2402-restricted manner and induced irrespective of hepatitis viral infection. The number of single hTERT epitope-specific T cells detected by ELISPOT assay was 10 to 100 specific cells per 3 x 10(5) PBMCs, and positive T cell responses were observed in 6.9% to 12.5% of HCC patients. hTERT-specific T cell responses were observed even in the patients with early stages of HCC. The frequency of hTERT/tetramer+ CD8+ T cells in the tumor tissue of patients with HCC was quite high, and they were functional. In conclusion, these results suggest that hTERT is an attractive target for T-cell-based immunotherapy for HCC, and the identified hTERT epitopes may be valuable both for immunotherapy and for analyzing host immune responses to HCC.
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PMID:Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. 1672 33

Using a newly developed assay of telomerase reverse transcriptase (hTERT) mRNA in serum by real-time RT-PCR, we previously reported this assay to be superior to other tumor markers for hepatoma. In this study, we aimed to clarify its clinical significance as a biomarker for lung cancer. In 112 patients with lung tumor and 80 individuals without cancer, we measured serum hTERT mRNA and epidermal growth factor receptor (EGFR) mRNA levels, using a quantitative one-step real-time RT-PCR assay. We examined its sensitivity and specificity in lung cancer diagnosis, its clinical significance in comparison with other tumor markers, and its correlation with the clinical parameters using multivariate analyses and correlation relative tests. The copy number of serum hTERT mRNA was independently correlated with tumor size, tumor number, presence of metastasis and recurrence, and smoking (all P < 0.05). EGFR mRNA correlated with tumor number and clinical stage (both P < 0.05). The sensitivity and specificity in lung cancer diagnosis were 89.0% and 72.7% for hTERT mRNA, and 71.3% and 80.0% for EGFR mRNA, respectively. hTERT mRNA was superior to other tumor markers in lung cancer diagnosis. For both mRNAs, serum levels were significantly correlated with levels in lung cancer tissues (both P < 0.05). The copy number of hTERT mRNA significantly decreased after the surgical treatment. The data suggest that hTERT mRNA, especially when combined with EGFR mRNA, is a novel and excellent biomarker for pulmonary malignancies to diagnose and assess the clinical stage.
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PMID:Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer. 1705 60

New progress has been made on the project "targeting gene-virotherapy of cancer" proposed by us, which is "targeting dual gene-virotherapy of cancer". By the use of two genes, all the xenograft tumors in nude mice could be completely eliminated. The researches have been published in international journals, such as Hepatology and Cancer Research (a highlight paper). In this study, a further superior strategy--"double targeting virus-dual gene therapy" was introduced. This strategy was specialized by the use of tumor specific promoter to control the tumor specific suppressor gene, such as alpha-fetoprotein (AFP), which controls hepatoma specific suppressor gene LFIRE or HCCS1. In addition, a second tumor specific promoter, such as hTERT or survivin was used to control E1A or E1B in the construct, as hTERT-E1A-AFP-E1B-HCCS1 or LFIRE, a double tumor specific promoter controlling hepatoma specific LFIRE or HCCS1 gene. By the combined use of this construct with a very strong antitumor construct, such as hTERT-E1A-AFP-E1B-IL-24, a strategy with both excellent tumor killing effect and excellent safety with very little damage to normal cells was obtained. Therefore, double targeting virus-dual gene therapy might be one of the most potential strategies for cancer treatment. Furthermore, a new type of interferon was also introduced, which might be an ideal antitumor drug.
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PMID:[A mini-review of targeting gene-virotherapy of cancer]. 1705 86

The curative treatments for hepatocellular carcinoma (HCC), including surgical resection and radiofrequency ablation (RFA), do not prevent tumour recurrence effectively. Dendritic cell (DC)-based immunotherapies are believed to contribute to the eradication of the residual and recurrent tumour cells. The current study was designed to assess the safety and bioactivity of DC infusion into tumour tissues following transcatheter hepatic arterial embolization (TAE) for patients with cirrhosis and HCC. Peripheral blood mononuclear cells (PBMCs) were differentiated into phenotypically confirmed DCs. Ten patients were administered autologous DCs through an arterial catheter during TAE treatment. Shortly thereafter, some HCC nodules were treated additionally to achieve the curative local therapeutic effects. There was no clinical or serological evidence of adverse events, including hepatic failure or autoimmune responses in any patients, in addition to those due to TAE. Following the infusion of (111)Indium-labelled DCs, DCs were detectable inside and around the HCC nodules for up to 17 days, and were associated with lymphocyte and monocyte infiltration. Interestingly, T lymphocyte responses were induced against peptides derived from the tumour antigens, Her-2/neu, MRP3, hTERT and AFP, 4 weeks after the infusion in some patients. The cumulative survival rates were not significantly changed by this strategy. These results demonstrate that transcatheter arterial DC infusion into tumour tissues following TAE treatment is feasible and safe for patients with cirrhosis and HCC. Furthermore, the antigen-non-specific, immature DC infusion may induce immune responses to unprimed tumour antigens, providing a plausible strategy to enhance tumour immunity.
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PMID:Combined therapy of transcatheter hepatic arterial embolization with intratumoral dendritic cell infusion for hepatocellular carcinoma: clinical safety. 1722 71

Currently available tumor markers for hepatocellular carcinoma (HCC) are alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and Des-gamma-carboxy prothrombin (DCP). However, their positive rate can not surpass abdominal ultrasonography (US) as modalities to detect small HCC at early stage, resulting in a possible delay of its diagnosis. There is a need to develop an additional sensitive marker to improve the early detection of HCC. We here introduced a newly developed quantitative detection method for serum hTERT mRNA, which has a clinical significance in HCC diagnosis. Briefly, we examined its sensitivity and specificity in HCC diagnosis, clinical significance in comparison with other tumor markers, and its correlations with the clinical parameters. Serum hTERT mRNA showed higher values in patients with HCC than those with chronic liver diseases. hTERT mRNA expression independently correlated with clinical parameters such as differentiation degree (p < 0.001). The sensitivity/specificity of hTERT mRNA in HCC diagnosis showed 88.2/70.0%. hTERT mRNA proved to be expectedly superior to AFP mRNA , AFP and DCP in HCC diagnosis. Importantly, hTERT mRNA in serum correlated with that in HCC tissue. Thus, we report that serum hTERT mRNA is a novel and available marker for HCC diagnosis.
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PMID:Development of a novel assay to quantify serum human telomerase reverse transcriptase messenger RNA and its significance as a tumor marker for hepatocellular carcinoma. 1808 81

The ginsenoside Rk1 is one of major components of heat-processed Panax ginseng C. A. MEYER, Sun Ginseng (SG). Here, we investigated the mechanisms underlying the anti-tumor activity of Rk1 in human hepatocellular carcinoma HepG2 cells in vitro. Rk1 markedly inhibited telomerase activity and cell growth along with significant morphological change. The expression levels of telomerase reverse transcriptase (hTERT) and c-Myc mRNA were obviously decreased with Rk1 treatment, while that of telomerase RNA (hTR) was not. Furthermore, Rk1 induced apoptosis through activation of caspases-8 and -3. However, Fas-associated death domain (FADD) expression decreased with Rk1 treatment, though it was known that the signaling cascade of FADD was associated with caspase-8 activity. Interestingly, activation of extracellular-regulated kinase (ERK) increased with Rk1 treatment. In conclusion, these results represent the first identification of the biological activity of Rk1 against HepG2 cell growth and show that the mechanism underlying the anti-tumor activity of Rk1 involves coordination between inhibition of telomerase activity and induction of apoptosis.
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PMID:Anti-tumor activity of the ginsenoside Rk1 in human hepatocellular carcinoma cells through inhibition of telomerase activity and induction of apoptosis. 1845 1

Human telomerase consisting of telomerase RNA template (hTR) and telomerase reverse transcriptase (hTERT) provides a mechanism for synthesis of telomere repeats that prolongs life span of cells. Telomerase activity is present in germ-line and malignant tumor cells but not in most normal human somatic cells. This study determined hTERT mRNA level in tissue samples from patients with gastrointestinal tract (GI) cancers. Tissue samples were obtained from 22 GI cancer patients, 3 gastrointestinal stomal tumors (GIST) and 25 corresponding non-cancerous tissues. hTERT expression was determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) using Taqman probe, hTERT mRNA was detected in 12 of 22 cancerous tissue samples. Six of 8 tissue samples obtained from patients with hepatocellular carcinoma and cholangiocarcinoma were positive for hTERT. However, hTERT mRNA was not detected in GIST and non-cancerous tissues. These results suggest that hTERT may be an effective target for cancer therapies to treat many type of GI cancers including cholangiocarcinoma and hepatocellular carcinoma.
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PMID:Detection of hTERT mRNA in gastrointestinal tract cancer specimens. 1856 21

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there is no effective treatment for HCC. It has been shown that sustained activation of telomerase is essential for the growth and progression of HCC, suggesting that telomerase is a rational target for HCC therapy. Here, we investigated the effects of siRNA-mediated knockdown of hTERT, the catalytic and rate-limiting subunit of telomerase, on the sensitivity of HCC cells to cisplatin. While silencing of hTERT and the resultant inhibition of telomerase activity by infection with the recombinant adenovirus expressing a hTERT siRNA (Ad-si/hTERT) alone did not affect the proliferation and viability of SMMC7721 and HepG2 HCC cells within five days, co-administration of Ad-si/hTERT, but not the empty adenovirus vector, with cisplatin caused much greater extent of apoptosis in vitro under the same conditions and induced significantly more robust inhibition of SMMC7721 and HepG2 tumors growth in a mouse tumor xenograft model than cisplatin monotherapy. Our results demonstrated the synergistic effect between hTERT siRNA and cisplatin in the suppression of HCC progression and indicated that the combination of hTERT-specific siRNA and cisplatin could be an effective therapy for HCC.
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PMID:siRNA-mediated inhibition of hTERT enhances chemosensitivity of hepatocellular carcinoma. 1870 58

The aim of this study was to use gene therapy via the Sleeping Beauty (SB) system to increase telomerase promoter activity to target hepatocellular carcinoma (HCC). In previous studies, we identified selective and increased expression of luciferase and suicide genes controlled by the hTERT (human telomerase reverse transcriptase) promoter and the SV40 enhancer in telomerase-positive cancer cell lines. Because telomerase is activated in about 80% of HCCs, it is likely that increasing the activity of the telomerase promoter with a suicide gene will effectively eradicate HCCs. We found that the telomerase promoter mediated SB system can efficiently insert transgene into HCC genomes. Also, telomerase promoter activity was increased using a SB vector expressing suicide gene HSV-TK (herpes simplex virus thymidine kinase) controlled by the hTERT promoter and a SV40 enhancer for the induction of telomerase-positive cancer-specific cell death. HCC cell lines transfected with pT.hTp.HSV-tk.Con with active helper plasmid and ganciclovir (GCV) significantly inhibited cancer cell growth. These results indicate that Sleeping Beauty transposon mediated suicide gene expression can be used in HCC-targeted cancer gene therapy.
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PMID:Sleeping Beauty-mediated suicide gene therapy of hepatocellular carcinoma. 1912 27


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