Forced Activation of β-Catenin Signaling Supports the Transformation of <i>hTERT</i>-Immortalized Human Fetal Hepatocytes

Wege, Henning; Heim, Denise; Lütgehetmann, Marc; Dierlamm, Judith; Lohse, Ansgar W.; Brümmendorf, Tim H.

doi:10.1158/1541-7786.mcr-10-0474

Cited by 15 publications

(16 citation statements)

References 38 publications

(42 reference statements)

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“…In this model, telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent (Wege et al 2011).…”

Section: R133 Review a Pestana And Others Tert Biology And Function Imentioning

confidence: 88%

“…Another study described that illegitimate activation of B-Catenin signalling enhances the transformation from immortalisation to malignant growth in human foetal hepatocytes (Wege et al 2011). In this model, telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent (Wege et al 2011).…”

Section: R133 Review a Pestana And Others Tert Biology And Function Imentioning

confidence: 92%

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TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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“…In this model, telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent (Wege et al 2011).…”

Section: R133 Review a Pestana And Others Tert Biology And Function Imentioning

confidence: 88%

Section: R133 Review a Pestana And Others Tert Biology And Function Imentioning

confidence: 92%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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“…Indeed, recent observations that constitutive expression of β-catenin increases cell cycle progression, and promotes full malignant transformation in TERT-immortalized human fetal hepatocytes, with up-regulation of genes mediating invasion and angiogenesis [49], attest to the significance of non-canonical telomerase activities during initiation and progression of cancer. In our study we observed that esophageal cancer cells expressing A279T had short telomeres relative to cells constitutively expressing wtTERT; these findings are consistent with observations by Vulliamy et al [22] that leukocytes from individuals with A279T genotype have short telomeres.…”

Section: Discussionmentioning

confidence: 99%

Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas

et al. 2014

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BackgroundAlthough implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.MethodsSequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability.ResultsSequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-β-catenin complex, markedly depleted β-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin™ exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage.ConclusionsA279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.

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“…This resembles the transcriptional program regulated by Wnt, a well known player in stem cell maintenance, cellular transformation and proliferation [51][52][53][54][55]. TERT acts as a transcription factor in β-catenin complexes.…”

Section: Regulation Of Gene Expression By Telomerasementioning

confidence: 96%

Telomerase and its extracurricular activities

Jaiswal

Kumar

Yadava

2013

Cellular and Molecular Biology Letters

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Abstract:The classical activity of telomerase is to synthesize telomeric repeats and thus maintain telomere length, which in turn ensures chromosome stability and cellular proliferation. However, there is growing evidence that implicates telomerase in many other functions that are independent of TERC being used as its template. Telomerase has an RNA-dependent RNA polymerase (RdRP) activity in the mitochondria. Other than viral RdRPs, it is the only RNAdependent RNA polymerase that has been identified in mammals. It also plays a role in the Wnt signaling pathway by acting as a transcriptional modulator. Telomerase acts as a reverse transcriptase independent of its core subunit, TERC. Studies indicate that telomerase is also involved in apoptosis and DNA repair.

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Forced Activation of β-Catenin Signaling Supports the Transformation of hTERT-Immortalized Human Fetal Hepatocytes

Cited by 15 publications

References 38 publications

TERT biology and function in cancer: beyond immortalisation

TERT biology and function in cancer: beyond immortalisation

Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas

Telomerase and its extracurricular activities

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