Ablation of galectin-3 induces p27(KIP1)-dependent premature senescence without oncogenic stress.
Ablation of galectin-3 induces p27(KIP1)-dependent premature senescence without oncogenic stress.
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DOI：
10.1038/cdd.2014.88
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发表时间：
2014-11
影响因子：
12.4
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由致癌刺激或肿瘤抑制因子激活诱导的早衰在肿瘤发生中起着相反的作用。在这里，我们提出，半乳糖凝集素-3，β-半乳糖苷结合凝集素，调节早衰没有致癌应激。我们在半乳糖凝集素-3敲除的MEFs和半乳糖凝集素-3缺失的胃癌细胞中检测到早衰、Skp 2降低和p27 KIP 1表达增加。有趣的是，半乳糖凝集素-3耗竭不影响其他衰老诱导物，如p14 ARF，p16 INK 4A和p21 WAF 1/CIP 1，表明半乳糖凝集素-3调节的衰老是p27 KIP 1依赖性的。我们证明，半乳糖凝集素-3耗竭减少视网膜母细胞瘤蛋白（Rb）磷酸化（Ser 780，Ser 807/811），细胞周期蛋白D1和CDK 4的表达，和E2 F1转录激活。半乳糖凝集素-3直接与细胞周期蛋白D1/CDK 4复合物相互作用并促进Rb的过度磷酸化。同时阻断E2 F1转录的抑制，从而增加Skp 2的表达，降低p27 KIP 1的稳定性，促进胃癌细胞的增殖。半乳糖凝集素-3耗尽的胃癌细胞的异种移植小鼠显示肿瘤生长迟缓，其通过Skp 2过表达逆转。半乳糖凝集素-3的表达增加还与晚期TNM（肿瘤、淋巴结、转移）系统、临床病理分期和淋巴结转移相关。Galectin-3高表达p27 KIP 1低表达的胃癌患者生存率明显降低。综上所述，我们的研究结果表明，半乳糖凝集素-3可能通过抑制过早衰老加速胃肿瘤的发生。
Premature senescence induced by oncogenic stimuli or tumor suppressor activation plays opposing roles in tumorigenesis. Here, we propose that galectin-3, a β-galactoside-binding lectin, regulates premature senescence without oncogenic stress. We detected premature senescence, decreased Skp2, and increased p27KIP1 expression in galectin-3 knockout MEFs and galectin-3-depleted gastric cancer cells. Interestingly, galectin-3 depletion did not affect other senescence inducers such as p14ARF, p16INK4A, and p21WAF1/CIP1, suggesting that galectin-3-regulated senescence is p27KIP1 dependent. We demonstrate that galectin-3 depletion decreases retinoblastoma protein (Rb) phosphorylation (Ser780, Ser807/811), cyclin D1 and CDK4 expression, and E2F1 transcriptional activation. Galectin-3 directly interacts with the cyclin D1/CDK4 complex and promotes hyperphosphorylation of Rb. It also blocks the inhibition of E2F1 transcription, thereby increasing the expression of Skp2 and reducing the stability of p27KIP1 to promote the proliferation of gastric cancer cells. Xenograft mice with galectin-3-depleted gastric cancer cells display tumor growth retardation that is reversed by Skp2 overexpression. Increased expression of galectin-3 is also associated with the advanced TNM (tumor, lymph node, metastasis) system, clinicopathological stage, and lymph node metastases. The probability of survival was significantly decreased in gastric cancer patients with galectin-3high p27KIP1-lowcells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence.
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