Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway

Abstract

Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.

Downregulation of miR-146b-3p Inhibits Proliferation and Migration and Modulates the Expression and Location of Sodium/Iodide Symporter in Dedifferentiated Thyroid Cancer by Potentially Targeting MUC20

“…MUC20 is over-expressed in many cancers, and has been shown to regulate cell growth, differentiation, metastasis, adhesion, and invasive immune surveillance. MUC20 is also an independent prognostic factor for the poor survival rate of malignant tumors ( 26 , 27 ). In thyroid cancer, studies have found that MUC1, MUC4, and MU15 are overexpressed in PTC.…”

Autophagy Regulatory Genes MET and RIPK2 Play a Prognostic Role in Pancreatic Ductal Adenocarcinoma: A Bioinformatic Analysis Based on GEO and TCGA

“…The mechanism prediction of MET and RIPK2 in our study provides clues for basic research. Some studies have found that MET promotes malignant phenotypes and contributes to tumor growth of PDAC [ 29 , 30 ]. But it is still unclear whether MET is associated with autophagy activity in PDAC.…”

Unsupervised Hierarchical Clustering of Pancreatic Adenocarcinoma Dataset from TCGA Defines a Mucin Expression Profile that Impacts Overall Survival

“…Among them, MUC1 and MUC4 have been extensively demonstrated to be oncomucins promoting tumor aggressiveness, proliferation, and metastasis [ 1 , 29 , 30 , 31 ], suggesting the potential use of their expression and methylation status as independent prognosis markers [ 32 , 33 , 34 ]. MUC16 and MUC20 have also been implicated in the malignant phenotype (cell viability, migration, and invasion) of PDAC cells [ 18 , 35 ]. MUC17 has been previously proposed as a potential prognosis molecular marker of PDAC [ 36 ].…”