Immuno-histochemical detection of human telomerase reverse transcriptase in human liver tissues

Abstract

Although telomerase activity in hepatocellular carcinoma (HCC) increases in accordance with degree of histological undi erentiation, it is unknown whether the level of telomerase activity in HCC re¯ects of the degree of activity in individual cells or the frequency of telomerasepositive HCC cells. Non-cancerous liver tissues exhibit low but signi®cant levels of telomerase activity, but the nature of telomerase-positive cells in these tissues is unclear. In this study, we performed immunohistochemical staining using speci®c antibody against telomerase reverse transcriptase (hTERT) protein in 15 HCC samples and 13 adjacent non-cancerous liver tissues. There were hTERT-positive hepatocytes, though very low frequency, in non-cancerous liver tissues. The frequencies in hTERT positive hepatocytes were very well correlated with clinicopathological parameters and telomerase activity levels: the average frequencies of chronic hepatitis was 0.2%, liver cirrhosis 0.2%, welldi erentiated HCC 3.0%, moderately di erentiated HCC 28%, and poorly di erentiated HCC 95%. The intensity of staining varied among cells within a given specimen, and correlation with degree of histological undi erentiation was less obvious. Portions of migrating lymphocytes and biliary epithelial cells were also hTERT-positive. These ®ndings indicate that the upregulation of telomerase activity with degree of undi erentiation of HCC is mainly due to the increase in frequency of hTERT positive HCC cells. Oncogene (2000) 19, 3888 ± 3893.

Telomerase-Dependent Virotherapy Overcomes Resistance of Hepatocellular Carcinomas against Chemotherapy and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand by Elimination of Mcl-1

“…Reactivation of telomerase activity is a characteristic molecular mechanism in hepatocarcinogenesis and it has been shown that hTERT is overexpressed in f80% to 100% of human HCCs (16)(17)(18). We and others recently showed that the hTERT-promoter can be used to generate tumor-specific replicating vectors for safe and effective virotherapy of telomerase-positive cancers (19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Telomerase activity and hTERT mRNA expression can be heterogeneous and does not correlate with telomere length in soft tissue sarcomas

“…28 The recent development of antibodies directed against hTERT, applicable to formalin-fixed, paraffin-embedded sections is very promising in identifying precisely which cells within a given tumor express hTERT. 29,30 Telomeric repeat lengths (TRF lengths) were measured in 2 different samples of all 37 STSs and an attempt was made to correlate TRF lengths with TA, hTERT mRNA expression, tumor histology, grade and proliferative activity. In every case, tumor TRF lengths were compared to normal striated muscle TRFs from 10 tumor-free patients, of which the mean size was 12 kbp.…”

hTERT associates with human telomeres and enhances genomic stability and DNA repair

“…One possibility is that hTERT interactions with telomeres may influence the association between telomeres and nuclear matrix. Recently, we and others have shown that hTERT is present throughout the nucleus but in certain instances hTERT is concentrated in the nucleolar organizing region (Tahara et al, 1999;Vaziri et al, 1999;Kawakaim et al, 2000;Wood et al, 2001;Etheridge et al, 2002). More directly, telomeres have been shown cytologically as well as biochemically to be tethered to the nuclear matrix (Smith and de Lange, 1997;Pandita, 2002).…”