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Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism

 Sun-Hyuk La  ;  Seok-Jun Kim  ;  Hyeok-Gu Kang  ;  Han-Woong Lee  ;  Kyung-Hee Chun 
 ONCOTARGET , Vol.7(35) : 57117-57130, 2016 
Journal Title
Issue Date
Animals ; Cell Line, Tumor ; Cell Proliferation ; Cellular Senescence* ; Fibroblasts/metabolism ; Galectin 3/genetics ; Galectin 3/metabolism* ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genetic Vectors ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Neoplasm Transplantation ; Phosphorylation ; Stomach Neoplasms/genetics* ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; Telomerase/genetics* ; Telomerase/metabolism* ; Treatment Outcome
cellular senescence ; galectin-3 ; gastric cancer ; hTERT ; telomerase
The human Telomerase Reverse Transcriptase (hTERT) gene encodes a rate-limiting catalytic subunit of telomerase that maintains genomic integrity. Suppression of hTERT expression could induce cellular senescence and is considered a potent approach for gastric cancer therapy. However, control of hTERT expression and function remains poorly understood in gastric cancer. In this study, we demonstrated that high expression levels of hTERT in malignant tissues are correlated with poor survival probability in gastric cancer patients. Knockdown of hTERT expression retarded cell proliferation and cellular senescence, which was confirmed by increased protein expression levels of p21cip1 and p27kip1, and decreased phosphorylation of Rb. In contrast, overexpression of hTERT increased cell proliferation and decreased cellular senescence. Remarkably, the down-regulation of hTERT expression was detected in lgals3-/- mouse embryo fibroblasts (MEFs). Knockdown of galectin-3 decreased the expression of hTERT in gastric cancer cells. Galectin-3 ablation-induced cellular senescence was rescued by concomitant overexpression of hTERT. hTERT ablation-induced cellular senescence and p21cip1 and p27kip1 expression was rescued by concomitant overexpression of galectin-3. The size of tumor burdens was increased in hTERT-overexpressed gastric cancer cells xenografted mice, whereas it was repressed by concomitant depletion of galectin-3. Additionally, we determined that the N-terminal domain of galectin-3 directly interacted with hTERT. The telomeric activity of hTERT was also decreased by galectin-3 ablation. Taken together, ablation of hTERT induces cellular senescence and inhibits the growth of gastric cancer cells, suggesting that it could be a potent target in gastric cancer therapy. We also propose that galectin-3 is an important regulator of hTERT expression and telomeric activity in gastric tumorigenesis.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Jun(김석준)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
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