Skip to main content
. 2020 Aug 19;10:1563. doi: 10.3389/fonc.2020.01563

FIGURE 4.

FIGURE 4

PTEN/PI3K/Akt/MMPs as a common signaling pathway contributes to matrix stiffness-caused metformin resistance. (A) (i,ii) Irrespective of metformin intervention or not, integrin β1 expression shows an obvious increase tendency in two HCC cells as matrix stiffness increases. (B) (i,ii) Knockdown of integrin β1 significantly upregulates the expressions of PTEN and partially inhibited the activation of the PI3K/Akt pathway in HCC cells grown on 16-kPa stiffness substrate. (C) (i,ii) Metformin intervention (27 mM for MHCC97H cells and 22 mM for Hep3B cells) had little effect on the expression of integrin β1 in HCC cells grown on 16 or 6-kPa stiffness substrates. (D) (i) MHCC97H cells grown on lower-stiffness substrate exhibited an obvious decrease in Akt phosphorylation after 27-mM metformin treatment for 24 h compared with the cells grown on a higher-stiffness substrate. (ii) Hep3B cells grown on a lower-stiffness substrate exhibited an obvious decrease in Akt phosphorylation after 22-mM metformin treatment for 24 h compared with the cells grown on higher-stiffness substrate. (E) PI3K inhibitor (LY294002, 20 μM) suppressed Akt phosphorylation and MMP2/MMP9 expression in HCC cells grown on the 16-kPa stiffness substrate. Error bar represents SEM, *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.