Hepatocellular carcinoma development is closely related to the changes in tissue mechanics induced by excess
collagen deposition and crosslinking, which leads to
liver fibrosis and malignant progression. The role of matrix stiffness has been widely assessed using various linearly elastic materials. However, the liver, like many soft tissues, also exhibits nonlinear elasticity by strain-stiffening, allowing cells to mechanically interact with their micromilieus which has attracted much attention in cellular processes recently. Here, we use a biomimetic
hydrogel grafting of
GRGDS peptide with tunable nonlinear mechanical properties, polyisocyanides (PIC), to investigate the influence of strain-stiffening on HepG2
liver cancer cell behavior by tuning PIC
polymer length. Compared to short PIC
polymer with lower critical stress, PIC
hydrogels composed of long
polymer with higher critical stress promote the motility and invasiveness of HepG2 cells, and induce more actin stress fibers and higher expression level of mechanotransducer YAP and its nuclear translocation. Strikingly, the expression of
calcium-activated potassium channel KCa3.1, an important
biomarker in
hepatocellular carcinoma, is also affected by the mechanical property of PIC
hydrogels. It was also shown that downregulating the KCa3.1 channel can be achieved by inhibiting the formation of actin fibers. Our findings imply that the strain-stiffening property of PIC
hydrogels affects the expression of KCa3.1
potassium channel via mediating cytoskeletal stress fiber formation, and ultimately influences the liver
carcinoma cell functional response. STATEMENT OF SIGNIFICANCE: The effect of nonlinear elasticity by strain-stiffening, is assessed in HepG2
liver cancer cell behavior by using a biomimetic
hydrogel with tunable mechanical properties, polyisocyanides (PIC). PIC
gels with higher critical stress promote the motility and invasiveness of HepG2 cells and induce upregulated expression levels of KCa3.1
potassium channel and YAP, but which can be suppressed by inhibiting the formation of actin fibers. Our findings imply that the strain-stiffening property of PIC
gels influences the expression of KCa3.1
potassium channel via mediating cytoskeletal stress fiber formation and, ultimately affects the liver
carcinoma cell functional response.