Abstract
BackgroundOur 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.MethodsWe investigated the potential role and mechanism of MSI2 in EGF-induced EMT in PC in vitro and vivo.ResultsEGF 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.ConclusionsMSI2 promotes EGF-induced EMT in PC via ZEB1-ERK/MAPK signaling.
Highlights
Our previous study showed Musashi2 (MSI2) promoted chemotherapy resistance and pernicious biology of pancreatic cancer (PC) by down-regulating Numb and p53
Western Blot (WB) showed that MSI2 protein level in both 2 PC cell lines in sg1MSI2 and sg2-MSI2 groups were significantly lower than that in corresponding scramble groups (Fig. 1b and c)
MSI2 silencing alone had no effect in cell morphology, but significantly inhibited EGFinduced epithelial-mesenchymal transition (EMT)-like cell morphology
Summary
Our previous study showed Musashi (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. Pancreatic cancer (PC) is one of the most malignant tumors in the world. From 2000 to 2011, the incidence rate and age-standardized mortality of PC in Chinese men have greatly increased, ranking the top first and second among malignant tumors [1]. In 2018, about 55,440 people were diagnosed with and about 44,340 died of PC in United States [2]. PC is predicted to become the second cancer related death in 2020 [3]. Aggressive local invasion and distant metastase contribute to the poor prognosis of PC patients which is significantly promoted by epithelial-mesenchymal transition (EMT) [4].
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