COL11A1-Driven Epithelial-Mesenchymal Transition and Stemness of Pancreatic Cancer Cells Induce Cell Migration and Invasion by Modulating the AKT/GSK-3β/Snail Pathway.

Hui Wang,Hong Ni,Xiaohong Shen,Huichao Zhou

doi:10.3390/biom12030391

Abstract

Background: Collagen type XI α1 (COL11A1) is associated with tumorigenesis and development in many human malignancies. Previous reports indicate that COL11A1 may be a significant diagnostic marker for pancreatic ductal adenocarcinoma (PDAC); however, its biological role in PDAC progression remains unclear. In this study, we investigated the influence of COL11A1 on the invasion and migration abilities of pancreatic cancer cells and explored its potential molecular mechanisms. Methods: Cell migration and invasion were assessed using Transwell assays in pancreatic cancer cells transfected with siCOL11A1 and pCNV3-COL11A1 plasmids. The protein and mRNA expression levels of N-cadherin, E-cadherin, Vimentin, cluster of differentiation (CD)-24, CD44, serine–threonine kinase (AKT), glycogen synthase kinase (GSK)-3β, phospho (p)-AKTSer473, p-GSK-3βSer9, and Snail were analyzed using Western blotting and real-time polymerase chain reaction (PCR). The effect of COL11A1 on cell stemness was tested using flow cytometry and clone formation assays. Results: These results demonstrated that COL11A1 significantly promoted the invasion and migration abilities of PDAC cells. Furthermore, COL11A1 facilitated the occurrence of epithelial–mesenchymal transition (EMT) and cell stemness by upregulating the expression levels of p-AKTSer473, p-GSK-3βSer9, and Snail. Conclusions: This study suggests that the activation of the AKT/GSK-3β/Snail signaling pathway induced by COL11A1 plays a major role in the progression of PDAC. Therefore, COL11A1 could serve as a potential target for PDAC treatment.

Highlights

Publisher’s Note: MDPI stays neutralPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors due to its propensity for early metastasis and local invasion [1,2]
We found that compared with the COL11A1 alone treatment group, the expression of E-cad was significantly upregulated, while the expression levels of N-cad, VIM, and Matrix Metalloproteinase (MMP)-2/9 were downregulated in the LY294002, siGSK-3β, and COL11A1 cotreatment group (Figure 5A)
The results suggested that AKT, glycogen synthase kinase (GSK)-3β, and Snail are necessary for COL11A1 immunofluorescence analysis of Snail expression by confocal microscopy in PANC-1 cells transto promote the motility and adhesion of pancreatic ductal adenocarcinoma (PDAC) cells (Figure 5D)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors due to its propensity for early metastasis and local invasion [1,2]. A histological hallmark characteristic of PDAC is the abundant extracellular matrix that constitutes its tumor microenvironment (TME). The TME is composed of a complex network of molecules with distinct biochemical properties that regulate tumor progression and metastasis. Among these components, collagen serves as a module of diverse signaling and is involved in the regulation of the physiological state in tumor cells [4].Recent evidence suggests that collagen type XI alpha 1 (COL11A1) is highly expressed in the invasive edge of pancreatic cancer tissues and is a novel biomarker associated with poor survival and chemoresistance in PDAC [5,6]. COL11A1 is closely involved in the migration with regard to jurisdictional claims in published maps and institutional affiliations

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Conclusion