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.

中文翻译：

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dysbindin通过miR-342-3p激活NF-κB/ MDM2来促进胰腺导管腺癌转移。

胰腺导管腺癌（PDAC）是最具侵入性的实体瘤之一，具有最高的与癌症相关的死亡率。尽管进行了深入的研究，但PDAC的侵袭性和病因学的分子机制仍然难以捉摸。MicroRNA（miRNA）是肿瘤细胞可塑性的关键调节因子，但尚未确定其在PDAC转移中的作用。我们的早期研究表明，与对照组相比，PDAC患者中的dysbindin蛋白水平升高，并且dysbindin的上调通过PI3K途径引起PDAC细胞增殖。在这里，我们显示dysbindin通过NF-κB/ MDM2信号轴促进了PDAC转移。dysbindin水平升高与PDAC中的侵袭性特征相关，dysbindin的过表达显着促进了PDAC的体内外转移和侵袭。出人意料的是，dysbindin被鉴定为miR-342-3p的直接靶标，它可促进NF-κB活化和PDAC转移。因此，dysbindin通过miR-342-3p介导的NF-κB激活代表了一种上下文相关的开关，该开关能够实现PDAC细胞增殖和转移。我们的数据表明，dysbindin和miR-342-3p是开发PDAC靶向疗法的潜在先导。