title: Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism.
abstract: 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.
authors: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors: Sun-Hyuk
authors: SH
authors: La
authors: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors: Seok-Jun
authors: SJ
authors: Kim
authors: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors: Hyeok-Gu
authors: HG
authors: Kang
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors: Han-Woong
authors: HW
authors: Lee
authors: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors: Kyung-Hee
authors: KH
authors: Chun
mesh_terms: D000818:Animals; D001798:Blood Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; C485095:Lgals3 protein, mouse; C509186:TERT protein, human; D019098:Telomerase
keywords: cellular senescence; galectin-3; gastric cancer; hTERT; telomerase