MUC4-promoted neural invasion is mediated by the axon guidance factor Netrin-1 in PDAC.
MUC4-promoted neural invasion is mediated by the axon guidance factor Netrin-1 in PDAC.
复制标题
MUC4促进的神经侵袭是由PDAC中的轴突引导因子Netrin-1介导的。
DOI：
10.18632/oncotarget.5668
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Wang L;Zhi X;Zhu Y;Zhang Q;Wang W;Li Z;Tang J;Wang J;Wei S;Li B;Zhou J;Jiang J;Yang L;Xu H;Xu Z
神经侵袭(NI)是胰腺导管腺癌(PDAC)的重要肿瘤学特征。然而，PDAC中NI的潜在机制仍不清楚。在这项研究中，我们发现MUC4在PDAC组织中过表达，高表达的MUC4比低表达的NI发生率更高。在体外背根神经节(DRG)-PDAC细胞共培养实验中，MUC4基因敲除抑制了PDAC细胞的迁移和侵袭，并损害了PDAC细胞沿神经的迁移。在体内，MUC4基因敲除抑制了小鼠NI模型中PDAC细胞的NI。在机制上，我们的数据显示，MUC4沉默导致Netrin-1表达减少，而在MUC4沉默的细胞中Netrin-1的重新表达拯救了NI的能力。此外，我们还发现，在MUC4沉默的细胞中，Netrin-1表达的降低是由于HER2/AKT/NF-κB通路下调所致。此外，MUC4基因敲除还导致pFAK、PSRC、pJNK和MMP9表达下调。综上所述，我们的发现揭示了MUC4通过Netrin-1通过HER2/AKT/NF-κB途径在PDAC中增强NI的新作用。
Neuralinvasion (NI) is an important oncological feature of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism of NI in PDAC remains unclear. In this study, we found that MUC4 was overexpressed in PDAC tissues and high expression of MUC4 indicated a higher NI incidencethan low expression. In vitro, MUC4 knockdown inhibited the migration and invasion of PDAC cells and impaired the migration of PDAC cells along nerve in dorsal root ganglia (DRG)-PDAC cell co-culture assay. In vivo, MUC4 knockdown suppressed the NI of PDAC cells in a murine NI model. Mechanistically, our data revealed that MUC4 silencing resulted in decreased netrin-1 expression and re-expression of netrin-1 in MUC4-silenced cells rescued the capability of NI. Furthermore, we identified that decreased netrin-1 expression was owed to the downregulation of HER2/AKT/NF-κB pathway in MUC4-silenced cells. Additionally, MUC4 knockdown also resulted in the downregulation of pFAK, pSrc, pJNK and MMP9. Taken together, our findings revealed a novelrole of MUC4 in potentiating NI via netrin-1 through the HER2/AKT/NF-κBpathway in PDAC.