Inhibition of matrix stiffness relating integrin β1 signaling pathway inhibits tumor growth in vitro and in hepatocellular cancer xenografts

Abstract

Background Cancer development is strictly correlated to composition and physical properties of the extracellular matrix. Particularly, a higher matrix stiffness has been demonstrated to promote tumor sustained growth. Our purpose was to explore the role of matrix stiffness in liver cancer development. Methods The matrix stiffness of tumor tissues was determined by atomic force microscopy (AFM) analysis. In vitro, we used a tunable Polyacrylamide (PA) hydrogels culture system for liver cancer cells culture. The expression level of integrin β1, phosphorylated FAK, ERK1/2, and NF-κB in SMMC-7721 cells was measured by western blotting analysis. We performed MTT, colony formation and transwell assay to examine the tumorigenic and metastatic potential of SMMC-7721 cells cultured on the tunable PA hydrogels. SMMC-7721 cancer xenografts were established to explore the anticancer effects of integrin inhibitors. Results Our study provided evidence that liver tumor tissues from metastatic patients possessed a higher matrix stiffness, when compared to the non-metastatic group. Liver cancer cells cultured on high stiffness PA hydrogels displayed enhanced tumorigenic potential and migrative properties. Mechanistically, activation of integrin β1/FAK/ ERK1/2/NF-κB signaling pathway was observed in SMMC-7721 cells cultured on high stiffness PA hydrogels. Inhibition of ERK1/2, FAK, and NF-κB signaling suppressed the pro-tumor effects induced by matrix stiffness. Combination of chemotherapy and integrin β1 inhibitor suppressed the tumor growth and prolonged survival time in hepatocellular cancer xenografts. Conclusion A higher matrix stiffness equipped tumor cells with enhanced stemness and proliferative characteristics, which was dependent on the activation of integrin β1/FAK/ERK1/2/NF-κB signaling pathway. Blockade of integrin signals efficiently improved the outcome of chemotherapy, which described an innovative approach for liver cancer treatment.

Extracellular matrix stiffness activates mechanosensitive signals but limits breast cancer cell spheroid proliferation and invasion

“…Our study also demonstrates that EGFR and the collagen-binding integrin α2β1 are both required for activation of ERK irrespective of ECM stiffness, and likely also contribute to YAP activity. Both receptor types have previously been suggested to contribute to ERK activity in cancer cells in 2D environments of differing stiffness ( Provenzano et al, 2009 ; Wang et al, 2021 ). Interestingly, our data shows that inhibiting both receptors reduced activity of ERK in both the outer and inner cells of spheroids.…”

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

“…However, the cause of the hypomethylation could not be clarified. BUC is associated with abnormal DNA methylation, and disruption of the methylation pattern establishment mechanism may result in deregulation of DNA methyltransferases and demethylases and altered metabolism of methyl groups [ 37 ]. In BUCs, several methyltransferases are upregulated [ 38 , 39 , 40 ]; their enhanced activity may result in depletion of methyl donors, thus potentially inducing an hypomethylation of gene promoters.…”

Extracellular matrix stiffness mediates radiosensitivity in a 3D nasopharyngeal carcinoma model

“…Integrin β1 is a crucial molecule for sensing stiffness. On high-stiffness PA hydrogels, the integrin β1/FAK/ERK1/2/NF-κB signaling pathway was reported to be activated in SMMC-7721 cells [ 55 ]. Therefore, it can be inferred from prior research and our experimental findings that integrin β1 play a key role in the radioresistance associated with ECM stiffness in 3D cultured cells.…”