Tissue stiffness contributes to YAP activation in bladder cancer patients undergoing transurethral resection

Abstract

Changes in the cellular microenvironment play a critical role in the development of bladder cancer (BC). Yes‐associated protein (YAP), a central mediator of the Hippo pathway, functions as a nuclear sensor of mechanotransduction that can be induced by stiffness of the extracellular matrix (ECM), including stiffness resulting from surgical manipulations. We aimed to clarify the possible association between surgically‐related ECM stiffness and YAP activation in BC patients. We compared 30 bladder cancer tissues with grade II (n = 15 recurrent and n = 15 newly diagnosed) with 30 adjacent healthy tissues. Atomic force microscopy showed that patients with recurrent BC had stiffer ECM than newly diagnosed patients (P < 0.05). Gene expression profiles showed that β1 integrin (ITGB1), focal adhesion kinase (FAK), CDC42, and YAP were upregulated in cancerous tissues (P < 0.05); additionally, β1 integrin activation was confirmed using a specific antibody. Nuclear localization of YAP was higher in recurrent cancerous tissues compared with newly diagnosed and it was positively associated with higher stiffness (P < 0.05). Our results suggest that postsurgery‐induced ECM stiffness can influence integrin–FAK–YAP activity and thereby YAP trafficking to the nucleus where it contributes to BC progression and relapse.

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

“…YAP is the prime mediator of the Hippo pathway, and its expression and cellular distribution were reported to be mechanically regulated by ECM stiffness (Ghasemi et al, 2020;Zhang et al, 2020) In the present study, we found that the expression of YAP in kidney was elevated in response to UUO. In addition, the results demonstrated that YAP could be activated by enhanced ECM stiffness and translocate to the nucleus, moreover, the inhibition of YAP impeded CTGF expression and ECM secretion.…”

Disrupted Surfaces of Porous Membranes Reduce Nuclear YAP Localization and Enhance Adipogenesis through Morphological Changes

“…The results indicate weakened cell-substrate interaction as well as reductions in YAP nuclear localization on all porous membranes, which is similar to the cellular behavior on soft substrates and tissues. 19,27,28 We also confirmed that surface disruption on rigid non-fouling micropatterned substrate yielded similar and consistent results. Since there is an increasing interest in utilizing disrupted surfaces in mesenchymal stem cell differentiation, 3,[29][30][31] we also evaluated whether the surface discontinuity of porous membranes could affect stem cell fate and the relationship to morphological changes in ADSCs.…”

ITGB1 enhances the Radioresistance of human Non-small Cell Lung Cancer Cells by modulating the DNA damage response and YAP1-induced Epithelial-mesenchymal Transition

“…In our study, depletion of YAP1 enhanced H460R radiosensitivity. YAP1 acts as a nuclear sensor for mechanotransduction, which can be induced by stiffness of the ECM [66]. We found that ITGB1 expression positively correlated with YAP1 expression and the two-gene expression signature correlated with the survival of patients with NSCLC.…”