hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation

Hu, C.; Ni, Zhenghong; Li, Bosheng; Xin, Yong; Yang, Xinquan; Zhang, Jianwei; Zhang, Dan; Qin, Yong; Jie, Meng-Meng; Dong, Hui; Li, Song; He, Fengtian; Yang, Shi‐Ming

doi:10.1136/gutjnl-2015-309322

Cited by 116 publications

(93 citation statements)

References 37 publications

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“…TERT induction/telomerase activation confers unlimited proliferation potential to cancer cells by stabilizing their telomere length, while recent observations reveal its multiple oncogenic activities independently of a telomerelengthening function, which include its effect on mitochondrial and ubiquitin-proteasomal function, DNA damage repair, gene transcription, microRNA expression, etc. [8][9][10][11][12][13][14][15][16]. Importantly, TERT was previously shown to promote the proliferation of normal mouse stem cells by recruiting chromatin-remodeling factor Brg1 to β-catenin target genes for their transcriptional activation [17]; and more recently, TERT was found to directly interact with β-catenin and robustly amplify its transcriptional outputs, thereby stimulating epithelial mesenchymal transformation (EMT) and stemness of cancer cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

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Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.

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Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

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“…hTERT promotes the proliferation of different types of cancer [19–22]. Previously, we observed that hTERT promotes the proliferation and invasion of gastric cancer via interactions with different genes [23–25]. In addition, the suppression of hTERT could also inhibit the malignant activity of gastric cancer [26, 27].…”

Section: Introductionmentioning

confidence: 99%

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway

et al. 2017

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BackgroundhTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells.ResultsExperiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2.Materials and MethodsImmunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP.ConclusionsWe may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.

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“…In gastric cancer, TERT was implicated in metastisation in several studies: (i) TERT-overexpressing cells had higher levels of Mac2-binding protein (Mac2BP) (Park et al 2007), a tumour antigen implicated in metastasis; (ii) TERT binds to c-MYC and recruits the complex to heparanase promoter to upregulate heparanase expression promoting invasion and metastasis of gastric cancer cells; furthermore, TERT-activated Wnt/B-Catenin signalling promotes c-MYC expression, which could in turn activate TERT transcription and expression in a positive feedback loop ; (iii) finally, it has been shown that TERT regulation of ITGB1 in the MDM2-FOXO3a-ITGB pathway is able to promote gastric cancer invasion (Hu et al 2015).…”

Section: Role Of Tert In Proliferation Invasion and Tumourigenesismentioning

confidence: 99%

“…Reduction of mtDNA damage Improvement of mitochondrial function Higher protection from apoptosis Prevention of nuclear DNA damage (Ahmed et al 2008) (Haendeler et al 2009) (Singhapol et al 2013) Cell death Nuclear TERT localization Diminished mtDNA damage Increase cell survival Protection against cellular senescence (Santos et al 2004) (Santos et al 2006) Nuclear TERT localization High DNA damage (Singhapol et al 2013) (Ding et al 2013) (Hu et al 2015) (Park et al 2007) ) ) ) ) (Liu et al 2013c) (Canela et al 2004) Invasion and metastisation TERT pathway selectively induces TERT mRNA expression in −146C > T mutant cells, in which the mutation creates a binding site specific for p52 that interacts with ETS factors ETS1/2 to mediate TERT reactivation (Li et al 2015b). This study also reports that there is an enhanced tumorigenic and proliferative effect due to NF-κB activation by the increase of telomerase activity dependent on the existence of −146C > T mutation (Li et al 2015b).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 99%

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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hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation

Abstract: The hTERT/MDM2-FOXO3a-ITGB1 pathway markedly contributes to hTERT-promoted gastric cancer invasion, suggesting that this pathway might be a novel target for the prevention and treatment of gastric cancer metastasis.

Cited by 116 publications

References 37 publications

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway

TERT biology and function in cancer: beyond immortalisation

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