Pin1/YAP pathway mediates matrix stiffness‐induced epithelial–mesenchymal transition driving cervical cancer metastasis via a non‐Hippo mechanism

Abstract

Cervical cancer metastasis is an important cause of death in cervical cancer. Previous studies have shown that epithelial–mesenchymal transition (EMT) of tumors promotes its invasive and metastatic capacity. Alterations in the extracellular matrix (ECM) and mechanical signaling are closely associated with cancer cell metastasis. However, it is unclear how matrix stiffness as an independent cue triggers EMT and promotes cervical cancer metastasis. Using collagen‐coated polyacrylamide hydrogel models and animal models, we investigated the effect of matrix stiffness on EMT and metastasis in cervical cancer. Our data showed that high matrix stiffness promotes EMT and migration of cervical cancer hela cell lines in vitro and in vivo. Notably, we found that matrix stiffness regulates yes‐associated protein (YAP) activity via PPIase non‐mitotic a‐interaction 1 (Pin1) with a non‐Hippo mechanism. These data indicate that matrix stiffness of the tumor microenvironment positively regulates EMT in cervical cancer through the Pin1/YAP pathway, and this study deepens our understanding of cervical cancer biomechanics and may provide new ideas for the treatment of cervical cancer.

PLAGL2 promotes bladder cancer progression via RACGAP1/RhoA GTPase/YAP1 signaling

“…Epithelial to mesenchymal transition (EMT) is a key process in the carcinogenesis of BCa, contributing to tumor invasiveness and distant metastasis [ 29 ]. Next, we investigated the effect of PLAGL2 on EMT by immunoblotting.…”

Cancer/testis-45A1 promotes cervical cancer cell tumorigenesis and drug resistance by activating oncogenic SRC and downstream signaling pathways

“…CT45A1 interacted with the key signaling protein kinase SRC and constitutively activated the oncoprotein protein in the absence of HPV and growth factors, resulting in activation of downstream tumorigenic CREB and YAP/TAZ signaling proteins. The transcription factor CREB and the transcription co-activators YAP/TAZ promote overexpression of a large numbers of oncogenic genes, consequently driving cervical cancer progression [ 40 – 45 ]. However, the mechanisms underlying activation of these transcription factor and co-activators in cancer are enigmatic.…”

Cellular elasticity in cancer: a review of altered biomechanical features

“…The present study contributes to the growing body of knowledge regarding the biomechanics of cervical cancer by demonstrating that the matrix stiffness of the tumor microenvironment positively regulates EMT in cervical cancer utilizing the yes-associated protein activity via the PPIase non-mitotic a-interaction 1 (Pin1/YAP) pathway. 187,188…”