Abstract
The tumor microenvironment plays a critical role in defining the growth and malignancy of solid tumors. Extracellular matrix (ECM) proteins such as collagen, vitronectin, and fibronectin are major components of the tumor microenvironment. Tumor growth-promoting reciprocal interaction between ECM and cytoplasmic proteins is regulated by the cell surface receptors called integrins. This study investigated the mechanism by which integrin β1 promotes pancreatic tumor growth. In MIA PaCa-2 pancreatic cancer cell line, the loss of integrin β1 protein reduced the ability of cells to proliferate in a 3D matrix and compromised the ability to form a focal adhesion complex. Decreased expression of integrin α5 was observed in KO cells, which resulted in impaired cell spreading and adhesion on vitronectin and fibronectin. Reduced expression of the integrin-associated protein, kindlin-2 was also recorded. The downregulation of kindlin-2 decreased the phosphorylation of Smad2/3 by reducing the expression of TGF-β receptor 2. These results unravel a new mechanism of integrin β1 in tumor growth by modifying the expression of kindlin-2 and TGF-β receptor 2 signaling.
Highlights
Increased Extracellular matrix (ECM) deposition in the tumor microenvironment is a characteristic of solid tumors, which promotes disease progression, interferes with patient prognosis, and is an obstacle for chemotherapeutic interventions
There is an increase in the expression of Integrin α5 in human pancreatic tumor patients compared to normal pancreatic tissues (p < 0.0001), it does not show any clear relationship with patient survival (p > 0.05)
We found that the TGF-β receptor 2 mRNA and protein expression were significantly reduced (50%, p < 0.001), in integrin β1 KO cells, compared expression were significantly reduced (50%, p < 0.001), in integrin β1 KO cells, compared to integrin β1 wild type (WT) cells (Figure 6C,D)
Summary
Increased ECM deposition in the tumor microenvironment is a characteristic of solid tumors, which promotes disease progression, interferes with patient prognosis, and is an obstacle for chemotherapeutic interventions. Integrin expression is higher in pancreatic tumor cells compared to normal tissues [2,3,4]. The mechanisms by which integrin promotes tumor growth in pancreatic cancer are unclear. Interaction of integrin with different cytosolic adaptor proteins is known to activate or inhibit various cellular signaling pathways. Kindlin-2 is one of these adaptor proteins that interacts with integrin and facilitates integrin activation and outside-in cellular signaling in normal epithelial cells [5,6,7]. Kindlin-2 is a prognostic marker as the mRNA level is higher in tumor tissues compared to normal pancreatic tissues [11,12,13]. Kindlin-2 is important in promoting multiple cellular signaling pathways promoting metastasis in pancreatic cancer
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