Stiff substrates increase YAP-signaling-mediated matrix metalloproteinase-7 expression

Abstract

Abnormally stiff substrates have been shown to trigger cancer progression. However, the detailed molecular mechanisms underlying this trigger are not clear. In this study, we cultured T84 human colorectal cancer cells on plastic dishes to create a stiff substrate or on collagen-I gel to create a soft substrate. The stiff substrate enhanced the expression of matrix metalloproteinase-7 (MMP-7), an indicator of poor prognosis. In addition, we used polyacrylamide gels (2, 67 and 126 kPa) so that the MMP-7 expression on the 126-kPa gel was higher compared with that on the 2-kPa gel. Next, we investigated whether yes-associated protein (YAP) affected the MMP-7 expression. YAP knockdown decreased MMP-7 expression. Treatment with inhibitors of epidermal growth factor receptor (EGFR) and myosin regulatory light chain (MRLC) and integrin-α2 or integrin-β1 knockdown downregulated MMP-7 expression. Finally, we demonstrated that YAP, EGFR, integrin-α2β1 and MRLC produced a positive feedback loop that enhanced MMP-7 expression. These findings suggest that stiff substrates enhanced colorectal cancer cell viability by upregulating MMP-7 expression through a positive feedback loop.

TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer

“…However, researchers had reported TNFAIP8 could adjust cell invasion‐related proteins VEGFR2, MMP1, and MMP9 levels in breast cancer cell line, but unfortunately the phenomenon did not be observed in lung cancer cells . In our experiment, we found MMP7 expression can be raised by TNFAIP8 and MMP7 can be regulated by hippo/Hippo pathway . We also tested the changes of EMT after TNFAIP8 overexpression or depletion, but no remarkable change was observed.…”

Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments

“…Additionally, while YAP/TAZ inhibition has been shown to influence cell proliferation [30], we do not believe that this significantly influenced cell spreading since all cultures were performed at low cell densities to prevent confounding factors such as cell-cell contacts. Previous work also correlated YAP/TAZ silencing [32] and lowered YAP/TAZ nuclear localization [33] with reduction in MMP activity. Since crosslink degradation is dependent on MMP activity and a precursor to spreading in our hydrogels, this could also explain the reduction in MSC spreading in 3D environments observed in response to VP treatment.…”

Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma

“…For example, the integrin-linked kinase (ILK) induced YAP/TAZ nuclear localization through suppression of the Hippo pathway via phospho-inhibition of MYPT1-PP1 and inactivation of Merlin [43]. Stiff substrates enhanced colorectal cancer cell viability by upregulating MMP-7 expression through a positive feedback loop containing YAP, EGFR, integrin-α2β1 and MRLC, independent of Hippo pathway [25]. α2β1 integrin can directly interact with CDH17 through its RGD motif [44], which causes β1 integrin activation and signaling to induce focal adhesion kinase and Ras activation, leading to colorectal cancer cells proliferation and liver metastasis [28].…”

“…They are activated when cells are grown on a stiff matrix while inactivated when cells are grown on a soft matrix [23, 24]. Integrins are adhesion receptors in cell–matrix adhesion and α2β1 integrin was shown to induce MMP-7 expression through activating YAP independent of Hippo pathway [25]. α2β1 integrin of the β1-integrin family is an extracellular matrix receptor for collagen and laminin [26].…”