Differential Expression of Full-length Telomerase Reverse Transcriptase mRNA and Telomerase Activity between Normal and Malignant Renal Tissues

Fan, Yi‐Ming; Liu, Zhaoxu; Fang, Xiaolei; Ge, Zheng; Guo, Nan; Jia, Yong; Sun, Peng; Lou, Fenglan; Björkholm, Magnus; Gruber, Astrid; Ekman, Peter; Xu, Dawei

doi:10.1158/1078-0432.ccr-05-0099

Cited by 48 publications

(40 citation statements)

References 35 publications

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“…21 However, inconsistent observations have been noted regarding a connection between cMyc and hTERT gene expression in RCC. 22,23 PKB/Akt can also affect telomerase expression through post-transcriptional phosphorylation of the hTERT protein as indicated in studies on myeloma and ovarian cancer cells. 24,25 Thus, the PI-3-kinase-PKB/Akt pathway can interact with hTERT and telomerase expression at both the transcriptional and posttranscriptional level and since DJ-1 might be a potentially important regulator of this pathway the present study was undertaken to further investigate this issue in RCC.…”

mentioning

confidence: 99%

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Sitaram

Cairney

Grabowski

et al. 2009

Intl Journal of Cancer

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DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p 5 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p 5 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p 5 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC. ' UICCKey words: renal cell carcinoma; DJ-1; cMyc; hTERT; telomere length; proliferation; prognosis Renal cell carcinoma (RCC) constitutes a heterogeneous group of tumors regarding cytogenetic aberrations, morphologic appearance and clinical outcome. The WHO classification identifies different morphologic subtypes of sporadic RCC including the three most common types, clear cell (ccRCC), papillary (pRCC) and chromophobe RCC. 1 Each entity shows characteristic cytogenetic abnormalities indicating essential differences between the RCC subtypes regarding the mechanisms leading to tumor development.The phosphatase tensin homologue deleted on chromosome 10 (PTEN) protein is a well known tumor suppressor acting as a negative regulator of the phosphoinositide-3 (PI-3)-kinase pathway including the downstream Protein Kinase B (PKB)/Akt protein. In RCC, an association between decreased PTEN expression and high PKB/Akt activation has been described. 2 A novel protein, DJ-1 (also called Cap1/RS/PARK7), has been proposed to be involved in tumorigenesis by negatively regulating PTEN. 3 DJ-1 was first described as a protein showing a cooperative transforming activity with H-Ras in mouse NIH3T3 cells. 4 Overexpression of DJ-1 has been reported in several malignancies, including breast and lung. 5,6 Further, DJ-1 mRNA expression levels seemed to be associated with survival in lung cancer 3 and elevated levels of circulating DJ-1 and anti-DJ-1 auto-antibodies were detected in breast cance...

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confidence: 99%

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Sitaram

Cairney

Grabowski

et al. 2009

Intl Journal of Cancer

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“…Alternatively spliced hTERT mRNA contributes to telomerase regulation under certain settings, and it has been established that the full-length hTERT transcripts, rather than any other variants, is translated into a functional protein required for active telomerase (5,6,(24)(25)(26)(27)(28)(29)(30). The recent study has indicated that hypoxia drives preferential expression of the full-length hTERT mRNA in ovary cancer cells (10).…”

Section: Discussionmentioning

confidence: 99%

“…It is known that the alternative splicing of hTERT transcription participates in controlling telomerase activity (5,(24)(25)(26)(27)(28)(29)(30)(31), and that a recent study suggests a transcriptional switch to the full-length hTERT mRNA in ovary cancer cells in response to hypoxia (10). Therefore, we asked whether this was the case in RCC cells by determining the expression profile of hTERT mRNA variants.…”

Section: Hypoxic Treatment Up-regulates Overall Htert Mrna Expressionmentioning

confidence: 99%

“…The PCR primer sequences specific for all the variants of hTERT mRNA (accession no. AF015950) were 5 ¶-CGGAAGAGTGTCTGGAGCAA-3 ¶ and 5 ¶-GGATGAA-GCGGAGTCTGGA-3 ¶ (24,29), and the resultant amplicon was 145 bp long. The amplification of the alternatively spliced hTERT mRNA was done with the primers 2164S (5 ¶-GCCTGAGCTGTACTTTGTCAA-3 ¶) and 2620AS (5 ¶-CGCAAACAGCTTGTTCTCCATGTC-3 ¶; refs.…”

Section: Rna Extraction and Rt-pcrmentioning

confidence: 99%

“…The amplification of the alternatively spliced hTERT mRNA was done with the primers 2164S (5 ¶-GCCTGAGCTGTACTTTGTCAA-3 ¶) and 2620AS (5 ¶-CGCAAACAGCTTGTTCTCCATGTC-3 ¶; refs. 24,25,29). This single primer set allowed detection of all differently spliced variants, including the full-length hTERT transcript simultaneously (25).…”

Section: Rna Extraction and Rt-pcrmentioning

confidence: 99%

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The Opposing Effect of Hypoxia-Inducible Factor-2α on Expression of Telomerase Reverse Transcriptase

Lou¹,

Chen

Jalink

et al. 2007

Molecular Cancer Research

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Hypoxia-inducible factor-1A (HIF-1A) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2A, the paralog of HIF-1A, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1A and HIF-2A were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2A led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2A. It was found that HIF-2A bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1A stimulated whereas HIF-2A inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2A resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1A activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2A enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells.

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Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers

Montero‐Conde

Leandro‐García

Martínez-Montes

et al. 2022

Clinical & Translational Med

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Background Comprehensive molecular studies on tumours are needed to delineate immortalization process steps and identify sensitive prognostic biomarkers in thyroid cancer. Methods and Results In this study, we extensively characterize telomere‐related alterations in a series of 106 thyroid tumours with heterogeneous clinical outcomes. Using a custom‐designed RNA‐seq panel, we identified five telomerase holoenzyme‐complex genes upregulated in clinically aggressive tumours compared to tumours from long‐term disease‐free patients, being TERT and TERC denoted as independent prognostic markers by multivariate regression model analysis. Characterization of alterations related to TERT re‐expression revealed that promoter mutations, methylation and/or copy gains exclusively co‐occurred in clinically aggressive tumours. Quantitative‐FISH (fluorescence in situ hybridization) analysis of telomere lengths showed a significant shortening in these carcinomas, which matched with a high proliferative rate measured by Ki‐67 immunohistochemistry. RNA‐seq data analysis indicated that short‐telomere tumours exhibit an increased transcriptional activity in the 5‐Mb‐subtelomeric regions, site of several telomerase‐complex genes. Gene upregulation enrichment was significant for specific chromosome‐ends such as the 5p, where TERT is located. Co‐FISH analysis of 5p‐end and TERT loci showed a more relaxed chromatin configuration in short telomere‐length tumours compared to normal telomere‐length tumours. Conclusions Overall, our findings support that telomere shortening leads to a 5p subtelomeric region reorganization, facilitating the transcription and accumulation of alterations at TERT‐locus.

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Differential Expression of Full-length Telomerase Reverse Transcriptase mRNA and Telomerase Activity between Normal and Malignant Renal Tissues

Cited by 48 publications

References 35 publications

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

The Opposing Effect of Hypoxia-Inducible Factor-2α on Expression of Telomerase Reverse Transcriptase

Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers

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