Dysbindin promotes pancreatic ductal adenocarcinoma metastasis by activating NF-κB/MDM2 via miR-342-3p.
Dysbindin promotes pancreatic ductal adenocarcinoma metastasis by activating NF-κB/MDM2 via miR-342-3p.
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DOI：
10.1016/j.canlet.2020.02.033
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发表时间：
2020-02
期刊：
影响因子：
9.7
通讯作者：
Donglie Zhu;Shi Zheng;Cheng Fang;Xin Guo;Dandan Han;Mingyao Tang;H. Fu;M. Jiang;N. Xie;Y. Nie;X. Yao;Yong Chen
中科院分区：
文献类型：
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作者：
Donglie Zhu;Shi Zheng;Cheng Fang;Xin Guo;Dandan Han;Mingyao Tang;H. Fu;M. Jiang;N. Xie;Y. Nie;X. Yao;Yong Chen
胰腺导管腺癌（PDAC）是最具侵袭性的实体瘤之一，具有最高的癌症相关死亡率。尽管进行了大量的研究，但PDAC的侵袭性和病因学的分子机制仍然难以捉摸。微小RNA（miRNAs）是肿瘤细胞可塑性的关键调节因子，但其在PDAC转移中的作用尚未被表征。我们的早期研究表明，与对照个体相比，PDAC患者中dysbindin蛋白水平升高，并且dysbindin通过PI 3 K途径上调PDAC细胞增殖。在这里，我们发现dysbindin通过NF-κB/MDM 2信号传导轴促进PDAC转移。dysbindin水平的增加与PDAC的侵袭性特征相关，并且dysbindin的过表达显著促进PDAC在体外和体内的转移和侵袭。令人惊讶的是，dysbindin被鉴定为促进NF-κB活化和PDAC转移的miR-342- 3 p的直接靶标。因此，dysbindin介导的NF-κB通过miR-342- 3 p的激活代表了一种环境依赖性开关，该开关使得PDAC细胞增殖和转移成为可能。我们的数据表明，dysbindin和miR-342- 3 p是PDAC靶向治疗发展的潜在先导。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid tumours and has the highest cancer-related mortality rate. Despite intense investigation, the molecular mechanisms underlying the invasiveness and aetiology of PDAC remain elusive. MicroRNAs (miRNAs) are key regulators of tumour cell plasticity, but their roles in PDAC metastasis have not been characterized. Our early studies showed that dysbindin protein levels are elevated in PDAC patients compared with control individuals and that dysbindin upregulation elicits PDAC cell proliferation via the PI3K pathway. Here, we show that dysbindin promoted PDAC metastasis via the NF-κB/MDM2 signalling axis. Increased dysbindin levels correlated with aggressive features in PDAC, and the overexpression of dysbindin significantly promoted PDAC metastasis and invasion in vitro and in vivo. Surprisingly, dysbindin was identified as a direct target of miR-342–3p, which promotes NF-κB activation and PDAC metastasis. Thus, dysbindin-mediated NF-κB activation via miR-342–3p represents a context-dependent switch that enables PDAC cell proliferation and metastasis. Our data suggest that dysbindin and miR-342–3p are potential leads for the development of targeted therapy for PDAC.