SIRT1 inhibits gastric cancer proliferation and metastasis via STAT3/MMP-13 signaling
SIRT1 inhibits gastric cancer proliferation and metastasis via STAT3/MMP-13 signaling
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SIRT1通过STAT3/MMP-13信号抑制胃癌增殖和转移
DOI：
10.1002/jcp.28186
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Zou, Xiaoping
中科院分区：
文献类型：
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作者：
Zhang, Shu;Yang, Yang;Zou, Xiaoping
胃癌的预后一直不佳，这是因为癌症有转移的倾向。沉默调节蛋白1（SIRT 1）作为信号转导和转录激活因子（STAT 3）信号转导的重要调节因子，在胃癌中的作用尚未完全阐明。在这里，我们报告了SIRT 1在胃癌患者组织中的表达上调。然而，我们发现，SIRT 1介导的耗竭增强了癌细胞的增殖和转移，并导致体内和体外实验中磷酸化STAT 3，乙酰化STAT 3和基质金属蛋白酶13（MMP-13）的富集。此外，我们证明了靶向SIRT 1缺失的癌细胞中STAT 3、AG 490和CL-821983的产生的小干扰RNA减少了转移。我们的研究结果表明，MMP-13表达与胃癌患者的淋巴结转移和不良生存结局相关。体内模型还显示，SIRT 1缺失通过STAT 3/MMP-13轴促进胃癌生长。总之，SIRT 1缺失通过激活STAT 3/MMP-13信号促进胃癌进展，表明SIRT 1可能具有肿瘤抑制作用。我们推测胃癌患者SIRT 1的上调可能是一种反馈机制的结果，该机制旨在对抗STAT 3信号的破坏作用。因此，SIRT 1激活剂可能成为转移性胃癌的预防和治疗药物。
Gastric cancer prognoses are persistently poor due to cancer's penchant to metastasize. As a crucial regulator of signal transducer and activator of transcription (STAT3) signaling, sirtuin 1's (SIRT1) function in gastric cancer has not been well understood. Here, we report upregulated expression of SIRT1 in tissues isolated from gastric cancer patients. However, we show that the depletion of SIRT1-mediated enhanced cancer cell proliferation and metastasis, and resulted in the enrichment of phosphorylated STAT3, acetylated STAT3, and matrix metalloproteinase 13 (MMP-13) in both in vivo and in vitro experiments. Additionally, we demonstrate that small interfering RNAs targeting the production of STAT3, AG490, and CL-821983 in cancer cells depleted of SIRT1 reduce metastasis. Our findings indicate that MMP-13 expression is associated with lymph node metastasis and poor survival outcomes in gastric cancer patients. In vivo models also showed that depleted SIRT1 promoted gastric cancer growth via the STAT3/MMP-13 axis. In conclusion, SIRT1 depletion encourages gastric cancer progression through the activation of STAT3/MMP-13 signaling, suggesting that SIRT1 may function as a tumor suppressor. We postulate that the upregulation of SIRT1 in gastric cancer patients may be the result of a feedback mechanism that aims to oppose the damaging effects of STAT3 signaling. As such, SIRT1 activators could potentially serve as preventive and therapeutic treatments for metastatic gastric cancer.