PAX8 Regulates Telomerase Reverse Transcriptase and Telomerase RNA Component in Glioma

Chen, Yu-Jen; Campbell, Heather; Wiles, Anna; Eccles, Michael R.; Reddel, Roger R.; Braithwaite, Antony W.; Royds, Janice A.

doi:10.1158/0008-5472.can-08-0058

Cited by 40 publications

(42 citation statements)

References 46 publications

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“…28 Considering PAX8 enhances telomerase activity, telomerase with macrophages tumors would be expected to be telomerase positive. 29 An increased content of nonmalignant cells provided by tumor-associated macrophages provides one explanation for why telomerase activity was not detected in telomerase with macrophages tumors.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 In vitro PAX8 upregulates the expression of a key protein in telomerase, hTERT, which increases telomerase activity in glioma cells suggesting PAX8 is associated with telomerase-positive glioblastoma. 29 Telomerase and non-defined telomere maintenance mechanism tumors share other similarities including a similar median patient age, similar overall survival that is poorer compared with alternative lengthening of telomere-positive tumors and infrequent TP53 and IDH1 mutations. [2][3][4] Investigated as a single group of non-alternative lengthening of telomeres tumors, non-defined telomere maintenance mechanism and telomerase-positive tumors responded to temozolomide.…”

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confidence: 99%

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Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

et al. 2016

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Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumorassociated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P = 0.0004, and telomerase with and without macrophages P = 0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs 476% for all other subtypes, P = 0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase-positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

et al. 2016

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“…Our data include glioblastoma and malignant meningioma amongst the cancers with a high incidence of PAX8-positive tumours. PAX8 transactivates the promoters of the telomerase catalytic subunit (hTERT) and the telomerase RNA component (hTR) to increase telomerase activity [17], and as might be predicted, the majority of the telomerase-positive tumours were also PAX8-positive. Therefore, in telomerase-positive glioblastomas, the PAX8 expression may play an important part in the immortalisation process by regulating telomerase activity.…”

Section: Discussionmentioning

confidence: 99%

“…All siRNAs were handled and prepared according to manufacturers’ instructions. The transfection experiments utilised A172 cells because of their endogenous PAX8 expression, as previously described [17]. Briefly, cells were plated at densities ranging from 2 × 10 4 to 1 × 10 5 cells/well 24 hours prior to transfection.…”

Section: Methodsmentioning

confidence: 99%

“…In earlier studies involving PAX8 and glioblastomas, we found increased PAX8 expression in tumours using a small panel of 14 telomerase-positive tumours and cell lines [14,17]. The tumour-promoting functions of PAX8 include the ability to transform cells and to form tumours in mice [18], an increased telomerase activity [17], and the promotion of cell cycle progression [19]. The genes upregulated by PAX8 include b cell lymphoma 2 (BCL2) and Wilms tumour 1 (WT1) .…”

Section: Introductionmentioning

confidence: 98%

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Increased paired box transcription factor 8 has a survival function in Glioma

et al. 2014

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BackgroundThe molecular basis to overcome therapeutic resistance to treat glioblastoma remains unclear. The anti-apoptotic b cell lymphoma 2 (BCL2) gene is associated with treatment resistance, and is transactivated by the paired box transcription factor 8 (PAX8). In earlier studies, we demonstrated that increased PAX8 expression in glioma cell lines was associated with the expression of telomerase. In this current study, we more extensively explored a role for PAX8 in gliomagenesis.MethodsPAX8 expression was measured in 156 gliomas including telomerase-negative tumours, those with the alternative lengthening of telomeres (ALT) mechanism or with a non-defined telomere maintenance mechanism (NDTMM), using immunohistochemistry and quantitative PCR. We also tested the affect of PAX8 knockdown using siRNA in cell lines on cell survival and BCL2 expression.ResultsSeventy-two percent of glioblastomas were PAX8-positive (80% telomerase, 73% NDTMM, and 44% ALT). The majority of the low-grade gliomas and normal brain cells were PAX8-negative. The suppression of PAX8 was associated with a reduction in both cell growth and BCL2, suggesting that a reduction in PAX8 expression would sensitise tumours to cell death.ConclusionsPAX8 is increased in the majority of glioblastomas and promoted cell survival. Because PAX8 is absent in normal brain tissue, it may be a promising therapeutic target pathway for treating aggressive gliomas.

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PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cells

Bougel

Renaud

Braunschweig

et al. 2009

The Journal of Pathology

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Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA. Its activity is not detectable in most somatic cells but it is reactivated during tumorigenesis. In most cancers, the combination of hTERT hypermethylation and hypomethylation of a short promoter region is permissive for low-level hTERT transcription. Activated and malignant lymphocytes express high telomerase activity, through a mechanism that seems methylationin-dependent. The aim of this study was to determine which mechanism is involved in the enhanced expression of hTERT in lymphoid cells. Our data confirm that in B cells, some T cell lymphomas and non-neoplastic lymph nodes, the hTERT promoter is unmethylated. Binding sites for the B cell-specific transcription factor PAX5 were identified downstream of the ATG translational start site through EMSA and ChIP experiments. ChIP assays indicated that the transcriptional activation of hTERT by PAX5 does not involve repression of CTCF binding. In a B cell lymphoma cell line, siRNA-induced knockdown of PAX5 expression repressed hTERT transcription. Moreover, ectopic expression of PAX5 in a telomerase-negative normal fibroblast cell line was found to be sufficient to activate hTERT expression. These data show that activation of hTERT in telomerase-positive B cells is due to a methylation-independent mechanism in which PAX5 plays an important role.

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PAX8 Regulates Telomerase Reverse Transcriptase and Telomerase RNA Component in Glioma

Cited by 40 publications

References 46 publications

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

Increased paired box transcription factor 8 has a survival function in Glioma

PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cells

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