The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility

Proctor, Andrew; Brownhill, Samantha; Burchill, Susan A.

doi:10.1016/j.bbadis.2009.02.011

Cited by 7 publications

(5 citation statements)

References 214 publications

(221 reference statements)

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“…The expression of hTERT closely correlates with telomerase activity and serves as an indicator of telomerase activation (9,10). Although previous studies have demonstrated that high hTERT expression is a predictive and prognostic biomarker of a poor outcome in a range of malignancies, including Ewing’s sarcoma, and colorectal, gastric and breast carcinoma (11–14), studies regarding the role of hTERT expression in esophageal cancer are sparse and thus warrant further investigation.…”

Section: Introductionmentioning

confidence: 99%

UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer

Guan¹,

Wang²,

Lei³

et al. 2015

Oncology Letters

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Human telomerase reverse transcriptase (hTERT) is a critical factor in unlimited cell proliferation and immortalization, with numerous studies demonstrating that high expression of hTERT is a poor prognostic factor in various types of cancer. Ubiquitin-conjugating enzyme E2D 3 (UBE2D3) is a member of the E2 family, and participates in the ubiquitin proteasome pathway to regulate basic cellular activities, such as cell cycle control, the DNA damage response, apoptosis, and tumorigenesis. Our previous study initially determined that downregulation of UBE2D3 expression increases hTERT expression and cell proliferation, however, the association between the expression of these two proteins and their functions in cancer tissues remains unknown. Therefore, the protein expression levels of hTERT and UBE2D3 were evaluated in 150 esophageal cancer and 30 adjacent healthy tissue samples by performing immunohistochemical analysis. Concurrently, the clinicopathological data of the enrolled patients were obtained to allow correlation analysis. It was identified that the expression of hTERT in the esophageal cancer tissues was significantly higher compared with that of the adjacent tissues (P=0.015), however, the expression of UBE2D3 was significantly lower in esophageal cancer tissues than the adjacent tissues (P=0.001). Additionally, the study demonstrated that hTERT was significantly upregulated in poorly-differentiated, advanced tumor-node-metastasis (TNM) stage cancer tissues (P<0.05 for all), however, UBE2D3 expression was downregulated in poorly-differentiated, lymph node invaded cancer tissues and recurrent cases. It was also identified that traditional factors, including tumor location, T stage, lymph node status, TNM stage, and molecular factors of hTERT and UBE2D3, were significantly associated with overall survival time (P<0.05 for all). Furthermore, UBE2D3, lymph node status and tumor location were independent prognostic factors for esophageal cancer in multivariate analysis. Most notably, hTERT and UBE2D3 expression were negatively correlated with each other. In conclusion, the findings of the present study indicated that hTERT and UBE2D3 proteins appear to be involved in the development of esophageal cancer, that UBE2D3 may a positive prognostic factor for esophageal cancer, and that UBE2D3 and hTERT expression levels are inversely correlated.

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Section: Introductionmentioning

confidence: 99%

UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer

Guan¹,

Wang²,

Lei³

et al. 2015

Oncology Letters

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“…ESFT occurs at all ages, although there is a peak incidence at 10–25 years of age. Recurrence and metastasis pose the greatest challenge for successful treatment of ESFT; patients in this cohort have a 20% or less 5-year disease-free survival rate (Proctor et al , 2009). There is therefore an urgent need for effective treatment strategies.…”

mentioning

confidence: 99%

Fenretinide-dependent upregulation of death receptors through ASK1 and p38α enhances death receptor ligand-induced cell death in Ewing's sarcoma family of tumours

White

Burchill

2010

Br J Cancer

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Background:Sustained p38MAPK phosphorylation upregulates p75 neurotrophin (p75NTR) and induces apoptosis in Ewing's sarcoma family of tumours (ESFT). As fenretinide induces ESFT death through sustained p38MAPK phosphorylation, we hypothesised that this may be effected through upregulation of death receptors (DRs) and that treatment of fenretinide plus DR ligands may enhance apoptosis.Methods:DR expression was determined by flow cytometry. Trypan blue exclusion assays, caspase-8 flow cytometry and immunoblotting for Bid were used to measure cell death.Results:Fenretinide upregulated cell surface expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, FAS and p75NTR, in an ASK1- and p38α-dependent manner. Cotreatment with fenretinide and DR ligands resulted in synergistic death compared with either agent alone; caspase-8 and Bid were cleaved in a time-dependent manner. Fenretinide did not increase DR expression in non-malignant cells. Furthermore, fenretinide, TRAIL or a combination of both agents was non-cytotoxic to non-malignant cells. Etoposide and actinomycin D increased expression of all DRs examined, whereas vincristine increased FAS alone. Only actinomycin D and TRAIL, and etoposide with TRAIL or FasL, enhanced death compared with either agent alone.Conclusion:The synergistic death observed with fenretinide and DR ligands suggests that this combination may be an attractive strategy for the treatment of ESFT.

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“…Dysregulation of telomerase activity results in uncontrolled malignant tumor growth [Dhaene et al, 2000]. Several studies have shown that cancer cells also have increased telomerase activity which stops telomere shortening and enhances their self‐renewal ability and resistance to apoptosis, effectively rendering them immortal [Fujiwara, 2009; Proctor et al, 2009; Schmelzer and Reid, 2009; Shaker et al, 2009].…”

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confidence: 99%

Cellular senescence and longevity of osteophyte‐derived mesenchymal stem cells compared to patient‐matched bone marrow stromal cells

Singh

Dhaliwal

Crawford

et al. 2009

J of Cellular Biochemistry

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This study aimed to determine the cellular aging of osteophyte-derived mesenchymal cells (oMSCs) in comparison to patient-matched bone marrow stromal cells (bMSCs). Extensive expansion of the cell cultures was performed and early and late passage cells (passages 4 and 9, respectively) were used to study signs of cellular aging, telomere length, telomerase activity, and cell-cycle-related gene expression. Our results showed that cellular aging was more prominent in bMSCs than in oMSCs, and that oMSCs had longer telomere length in late passages compared with bMSCs, although there was no significant difference in telomere lengths in the early passages in either cell type. Telomerase activity was detectable only in early passage oMSCs and not in bMSCs. In osteophyte tissues telomerase-positive cells were found to be located perivascularly and were Stro-1 positive. Fifteen cell-cycle regulator genes were investigated and only three genes (APC, CCND2, and BMP2) were differentially expressed between bMSC and oMSC. Our results indicate that oMSCs retain a level of telomerase activity in vitro, which may account for the relatively greater longevity of these cells, compared with bMSCs, by preventing replicative senescence.

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The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility

Cited by 7 publications

References 214 publications

UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer

UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer

Fenretinide-dependent upregulation of death receptors through ASK1 and p38α enhances death receptor ligand-induced cell death in Ewing's sarcoma family of tumours

Cellular senescence and longevity of osteophyte‐derived mesenchymal stem cells compared to patient‐matched bone marrow stromal cells

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