Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling
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(2020) 39:16
RESEARCH
Open Access
Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling Weiwei Sheng1†, Xiaoyang Shi1†, Yiheng Lin1, Jingtong Tang1, Chao Jia1, Rongxian Cao2, Jian Sun1, Guosen Wang3, Lei Zhou4 and Ming Dong1*
Abstract 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 ZEB1ERK/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. Keywords: Musashi2, EGF, ZEB1, ERK/MAPK pathway, C-Myc, Epithelial mesenchymal transition, Pancreatic cancer
Background 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 now 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]. PC * Correspondence: [email protected] † Weiwei Sheng and Xiaoyang Shi contributed equally to this work. 1 Department of Gastrointestinal Surgery, the First Hospital, China Medical University, Shenyang 110001, China Full list of author information is available at the end of the article
stimulated by EMT loses epithelial character, gains strong invasive mesenchymal cells, and finally transforms into the highly malignant phenotype [2, 5]. Musashi RNA-binding protein 2 (MSI2) is a translational repressor identified in Drosophila melanogaster. It plays a significant role in regulating asymmetric division, stemness maintenance and neural differentiation, hematopoi
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