Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer

Hu, Hua; Zhang, Yang; Mei, Zou; Yang, Shuai; Liang, Xin

doi:10.1007/s00432-010-0795-x

Cited by 63 publications

(59 citation statements)

References 34 publications

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“…These findings indicate an interaction between positive and negative factors in the maintenance of TL in plasma cell disorders and support a role for TRF2 and TANK1 upregulation in disease progression. In a related study of gastric cancer, a significantly higher expression of TRF2 in tumor tissue and in lymph-node metastasis compared with precancerous lesions and normal gastric mucosa was found (28). Changes in telomeric gene expression and their negative correlations with telomere reduction, observed in our series, suggest that mechanisms other than telomerase activation are involved in TL maintenance in plasma cell disorders.…”

Section: Discussionsupporting

confidence: 62%

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Panero

Arbelbide

Fantl

et al. 2010

Mol Med

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In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT ) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.

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Section: Discussionsupporting

confidence: 62%

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Panero

Arbelbide

Fantl

et al. 2010

Mol Med

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“…Therefore, it was hypothesized that high or low protein expression may induce instability of shelterin, which may lead to the occurrence of malignant tumors. In a previous study by the present authors, it was detected that TIN2 protein expression was higher in the precancerous lesion, gastric cancer and metastasis groups compared with the normal group (18). Furthermore, the expression of TIN2 protein was higher in the gastric cancer and metastasis groups compared with the precancerous group (18).…”

Section: Introductionsupporting

confidence: 52%

“…In a previous study by the present authors, it was detected that TIN2 protein expression was higher in the precancerous lesion, gastric cancer and metastasis groups compared with the normal group (18). Furthermore, the expression of TIN2 protein was higher in the gastric cancer and metastasis groups compared with the precancerous group (18). Therefore, it was hypothesized that abnormal TIN2 expression may induce shelterin instability, thereby leading to the occurrence of malignant tumors.…”

Section: Introductionmentioning

confidence: 45%

Effects of TIN2 on telomeres and chromosomes in the human gastric epithelial cell line GES-1

Yang

et al. 2018

Oncol Lett

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Abstract. TERF1-interacting nuclear factor 2 (TIN2) is a key member of the protein complexes that protect telomeres. TIN2 contributes an important role in biological processes. In a previous study by the present authors, an association was reported between high TIN2 protein expression and gastric cancer. Therefore, it was hypothesized that abnormal TIN2 expression may cause the development of malignancies, including, gastric carcinomas. To investigate this hypothesis, the present study employed peptide nucleic acid fluorescence in situ hybridization technology to analyze the human gastric epithelial GES-1 cells with high TIN2 expression or inhibited TIN2 expression. The results indicated that GES-1 cell lines with high TIN2 expression exhibited greater telomere dysfunction-induced damage compared with GES-1 cell lines with inhibited TIN2 expression. Chromosome analysis indicated that GES-1 cells with high TIN2 expression exhibited 2.48±1.30 aberrant chromosomal changes per 100 cells, that may contribute to telomere DNA damage. Therefore, aberrant chromosomal alterations may provide a novel perspective for the pathogenesis of gastric cancer.

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“…We were particularly interested in CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML because they had been shown to play negative roles in GC proliferation and growth. [18][19][20][21][22][23][24] To verify the effects of methylation changes on the expression of these genes, we examined the methylation status of the promoter regions using methylation-specific PCR in MKN45 cells transfected with shUHRF1, SGC7901 cells with UHRF1 and their negative controls. As shown in Figure 4A, UHRF1 inhibition reversed the promoter methylation of all these genes and upregulation of UHRF1 enhanced promoter methylation.…”

Section: Tumor Suppressors Contribute To Uhrf1-induced Growth Inhibitionmentioning

confidence: 99%

UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation

Zhou

Shang

Jin³

et al. 2015

Cancer Biology & Therapy

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Epigenetic changes play significant roles in cancer development. UHRF1, an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene (TSG) silencing in several cancers. In a previous study, we found that UHRF1 promoted gastric cancer (GC) invasion and metastasis. However, the role and underlying mechanism of UHRF1 in GC carcinogenesis remain largely unknown. In the present study, we investigated UHRF1 expression and function in GC proliferation and explored its downstream regulatory mechanism. The results demonstrated that UHRF1 overexpression was an independent and significant predictor of GC prognosis. Downregulation of UHRF1 suppressed GC proliferation and growth in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Furthermore, downregulation of UHRF1 reactivated 7 TSGs, including CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML, via promoter demethylation. These results provide insight into the GC proliferation process, and suggest that targeting UHRF1 represents a new therapeutic approach to block GC development.

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Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer

Cited by 63 publications

References 34 publications

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Effects of TIN2 on telomeres and chromosomes in the human gastric epithelial cell line GES-1

UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation

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