MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression

Author:

Huang Longping1,Sun Jian1,Ma Yuteng1,Chen He2,Tian Chen1,Dong Ming1

Affiliation:

1. First Hospital of China Medical University

2. The Fourth People's Hospital of Shenyang

Abstract

Abstract

Background: The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. Methods: In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. Results: Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Conclusions: Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

Publisher

Springer Science and Business Media LLC

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