Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism.
Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism.
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DOI：
10.18632/oncotarget.10986
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发表时间：
2016-08-30
期刊：
影响因子：
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通讯作者：
Chun KH
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文献类型：
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作者：
La SH;Kim SJ;Kang HG;Lee HW;Chun KH
人端粒酶逆转录酶（hTERT）基因编码端粒酶的限速催化亚基，其维持基因组的完整性。抑制hTERT表达可诱导细胞衰老，被认为是治疗胃癌的有效方法。然而，在胃癌中对hTERT表达和功能的控制仍然知之甚少。在这项研究中，我们证明了hTERT在恶性组织中的高表达水平与胃癌患者的生存率低相关。hTERT表达的敲低延缓细胞增殖和细胞衰老，这通过p21 cip 1和p27 kip 1蛋白表达水平的增加以及Rb磷酸化的降低来证实。相反，hTERT的过表达增加了细胞增殖并降低了细胞衰老。值得注意的是，在lgals 3 −/−小鼠胚胎成纤维细胞（MEFs）中检测到hTERT表达的下调。Galectin-3基因敲低可降低胃癌细胞hTERT的表达。半乳糖凝集素-3消融诱导的细胞衰老被hTERT的伴随过度表达所拯救。hTERT消融诱导的细胞衰老和p21 cip 1和p27 kip 1的表达被半乳糖凝集素-3的伴随过度表达所拯救。hTERT过表达的胃癌细胞异种移植小鼠的肿瘤负荷的大小增加，而它被半乳糖凝集素-3的伴随消耗抑制。此外，我们确定半乳糖凝集素-3的N-末端结构域直接与hTERT相互作用。半乳糖凝集素-3的消融也降低了hTERT的端粒活性。总之，hTERT的消融诱导细胞衰老和抑制胃癌细胞的生长，这表明它可能是胃癌治疗的有效靶点。我们还提出，半乳糖凝集素-3是一个重要的调节剂的hTERT表达和端粒活性在胃肿瘤的发生。
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.