Cell type specificity on integrin α2 mediated functions in pancreatic cancer

Abstract

BackgroundAmong the various cancers, pancreatic cancer has the third highest mortality rate per 100,000 population each year. In 2021, an estimated 60,430 people will be diagnosed with pancreatic cancer in the United States, with more than 48,220 deaths. Desmoplasia is a hallmark of pancreatic cancer. Cell surface receptor integrin promotes tumor progression by modulating the reciprocal signaling between the actin‐cytoskeleton and the desmoplastic tumor microenvironment. Integrin’s are heterodimeric cell surface receptors consisting of non‐covalently associated α and β subunits. Integrin β1 forms heterodimers with 12 different α subunits, and its expression is upregulated in pancreatic cancer. Integrin α2 is one of the α subunits that shows both pro and anti‐tumorigenic properties in cancer and belongs to the I domain group of integrin where the I domain in α subunit mediates the binding to matrix proteins. This study tested the hypothesis that in pancreatic cancer, upregulation of integrin β1 differentially regulates integrin α2 mediated cell functions in a cell‐specific manner.MethodTwo of the major pancreatic cancer types, Mia Paca‐2 and Panc‐1 cell lines were used in this study. The protein level of integrin β1 was downregulated using genetic approaches and confirmed by immunoblotting, immunocytochemistry, and qRT‐PCR. Cell spreading and adhesion assays were performed with WT cells and clones with lower integrin β1 expression. Cells were grown on the 3D matrix to see the ability of cells to proliferate in the presence of matrix proteins.ResultsDownregulation of integrin β1 in both Mia Paca‐2 and Panc‐1 cells decreased tumor growth in the collagen‐Matrigel 3D matrix significantly (n=10, p<0.0001). With the reduction of expression of integrin β1, there is a significant decrease in the expression of integrin α5 in Mia paca‐2 and Panc‐1 cell, which resulted in a significant decrease in cell adhesion (n=3; P<0.05) and spreading (n=40; p<0.05) on fibronectin and vitronectin. However, there were contrasting results in the case of integrin α2 expression and functions with integrin β1 downregulation. An increase in integrin α2 expression was recorded in Miapaca‐2 cells (n=3, p<0.05) with increased cell adhesion (n=3; p<0.05) and cell spreading (n=3; p<0.05) on collagen‐1 by the deletion of integrin β1. In the case of Panc‐1, there is reduced expression of integrin α2 that resulted in decreased cell adhesion (n=3; p<0.05) and cellular spreading (n=30; p<0.05) on collagen 1 with the knock‐down of integrin β1.ConclusionThe results indicate that the tumor suppressor property of integrin α2 varies between different tumor types in pancreatic cancer. Further studies are required to understand the mechanism of the anti‐tumorigenic property of integrin α2 in pancreatic cancer.