Musashi2 promotes the progression of pancreatic cancer through a novel ISYNA1-p21/ZEB-1 pathway

Lei Zhou; WeiWei Sheng; Chao Jia; Xiaoyang Shi; Rongxian Cao; Guosen Wang; Yiheng Lin; Fang Zhu; Qi Dong; Ming Dong

doi:10.1111/jcmm.15676

Musashi2 promotes the progression of pancreatic cancer through a novel ISYNA1-p21/ZEB-1 pathway

J Cell Mol Med. 2020 Sep;24(18):10560-10572. doi: 10.1111/jcmm.15676. Epub 2020 Aug 11.

Authors

Lei Zhou¹, WeiWei Sheng¹, Chao Jia¹, Xiaoyang Shi¹, Rongxian Cao¹, Guosen Wang¹, Yiheng Lin¹, Fang Zhu², Qi Dong³, Ming Dong¹

Affiliations

¹ Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
² Division of Cardiology, The People's Hospital of Liaoning Province, Shenyang, China.
³ Department of General Surgery, The People's Hospital of Liaoning Province, Shenyang, China.

Abstract

Our previous studies found overexpression of Musashi2 (MSI2) conduced to the progression and chemoresistance of pancreatic cancer (PC) by negative regulation of Numb and wild type p53 (wtp53). Now, we further investigated the novel signalling involved with MSI2 in PC. We identified inositol-3-phosphate synthase 1 (ISYNA1) as a novel tumour suppressor regulated by MSI2. High MSI2 and low ISYNA1 expression were prevalently observed in 91 PC tissues. ISYNA1 expression was negatively correlated with MSI2 expression, T stage, vascular permeation and poor prognosis in PC patients. What's more, patients expressed high MSI2 and low ISYNA1 level had a significant worse prognosis. And in wtp53 Capan-2 and SW1990 cells, ISYNA1 was downregulated by p53 silencing. ISYNA1 silencing promoted cell proliferation and cell cycle by inhibiting p21 and enhanced cell migration and invasion by upregulating ZEB-1. However, MSI2 silencing upregulated ISYNA1 and p21 but downregulated ZEB-1, which can be rescued by ISYNA1 silencing. Moreover, reduction of cell migration and invasion resulting from MSI2 silencing was significantly reversed by ISYNA1 silencing. In summary, MSI2 facilitates the development of PC through a novel ISYNA1-p21/ZEB-1 pathway, which provides new gene target therapy for PC.

Keywords: ISYNA1; MSI2; cell biology; pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / mortality
Carcinoma, Pancreatic Ductal / pathology*
Carcinoma, Pancreatic Ductal / secondary
Cell Line, Tumor
Cell Movement
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / physiology*
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Intramolecular Lyases / antagonists & inhibitors
Intramolecular Lyases / biosynthesis
Intramolecular Lyases / genetics
Intramolecular Lyases / physiology*
Kaplan-Meier Estimate
Liver Neoplasms / secondary
Lymphatic Metastasis
Male
Middle Aged
Neoplasm Invasiveness
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / pathology*
Prognosis
RNA Interference
RNA, Small Interfering / genetics
RNA, Small Interfering / pharmacology
RNA-Binding Proteins / physiology*
Signal Transduction / physiology*
Tumor Suppressor Protein p53 / physiology
Zinc Finger E-box-Binding Homeobox 1 / biosynthesis
Zinc Finger E-box-Binding Homeobox 1 / genetics
Zinc Finger E-box-Binding Homeobox 1 / physiology*

Substances

CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
MSI2 protein, human
Neoplasm Proteins
RNA, Small Interfering
RNA-Binding Proteins
TP53 protein, human
Tumor Suppressor Protein p53
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1
Intramolecular Lyases
D-myo-inositol-3-phosphate synthase