BACKGROUND Our previous study showed Musashi2 (MSI2) promoted chemotherapy resistance and pernicious biology of pancreatic cancer (PC) by down-regulating Numb and p53. We further explored the novel molecular mechanism involving its oncogenic role in PC development. METHODS We investigated the potential role and mechanism of MSI2 in EGF-induced EMT in PC in vitro and vivo. RESULTS EGF enhanced EGFR (epidermal growth factor receptor) phosphorylation, induced EMT and activated ZEB1-ERK/MAPK signaling in 2 PC cells. However, MSI2 silencing reversed EGF stimulated function, including inhibiting EGF-promoted EMT-like cell morphology and EGF-enhanced cell invasion and migration. Meanwhile, MSI2 silencing inhibited EGF-enhanced EGFR phosphorylation at tyrosine 1068 and reversed EGF-induced change of the key proteins in EMT and ZEB1-ERK/MAPK signaling (ZEB1, E-cad, ZO-1, β-catenin, pERK and c-Myc). Additionally, MSI2 was co-stained and co-immunoprecipitated with ZEB1, pERK and c-Myc in PC cells by IF and co-IP, implying a close interaction between them. In vivo, MSI2 silencing inhibited pancreatic tumor size in situ and distant liver metastases. A close relationship of MSI2 with EMT and ZEB1-ERK/MAPK signaling were also observed in vivo and human PC samples, which coordinately promoted the poor prognosis of PC patients. CONCLUSIONS MSI2 promotes EGF-induced EMT in PC via ZEB1-ERK/MAPK signaling.

中文翻译：

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Musashi2通过ZEB1-ERK / MAPK信号传导在胰腺癌中促进EGF诱导的EMT。

背景：我们先前的研究表明，Musashi2（MSI2）通过下调Numb和p53来促进胰腺癌（PC）的化疗耐药性和有害生物学。我们进一步探索了涉及其在PC开发中的致癌作用的新型分子机制。方法我们研究了MSI2在EGF诱导的PC体内和体外EMT中的潜在作用和机制。结果EGF增强了2个PC细胞中EGFR（表皮生长因子受体）的磷酸化，诱导了EMT并激活了ZEB1-ERK / MAPK信号传导。但是，MSI2沉默可逆转EGF刺激的功能，包括抑制EGF促进的EMT样细胞形态和EGF增强的细胞侵袭和迁移。与此同时，MSI2沉默抑制酪氨酸1068处EGF增强的EGFR磷酸化，并逆转EGF诱导的EMT和ZEB1-ERK / MAPK信号传导关键蛋白（ZEB1，E-cad，ZO-1，β-catenin，pERK和c-Myc）的变化）。另外，通过IF和co-IP在PC细胞中将MSI2与ZEB1，pERK和c-Myc共染色并共免疫沉淀，这意味着它们之间存在紧密的相互作用。在体内，MSI2沉默可抑制胰腺肿瘤的原位和远处肝转移。在体内和人PC样品中还观察到MSI2与EMT和ZEB1-ERK / MAPK信号传导密切相关，这协调地促进了PC患者的不良预后。结论MSI2通过ZEB1-ERK / MAPK信号传导促进PC中EGF诱导的EMT。通过IF和co-IP，PC细胞中的pERK和c-Myc相互暗示。在体内，MSI2沉默可抑制胰腺肿瘤的原位和远处肝转移。在体内和人PC样品中还观察到MSI2与EMT和ZEB1-ERK / MAPK信号传导密切相关，这协调地促进了PC患者的不良预后。结论MSI2通过ZEB1-ERK / MAPK信号传导促进PC中EGF诱导的EMT。通过IF和co-IP，PC细胞中的pERK和c-Myc相互暗示。在体内，MSI2沉默可抑制胰腺肿瘤的原位和远处肝转移。在体内和人PC样品中还观察到MSI2与EMT和ZEB1-ERK / MAPK信号传导密切相关，这协调地促进了PC患者的不良预后。结论MSI2通过ZEB1-ERK / MAPK信号传导促进PC中EGF诱导的EMT。