A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model

Abstract Keloids, tumor-like lesions that result from excessive scar formation, have no definitive treatment modality. Activation of c-mesenchymal-epithelial transition factor (c-Met) promotes cell proliferation and survival. Selective c-Met inhibitors, such as PHA-665752, may attenuate the activity...

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Autores principales:	Min-Ha Choi, Jinhyun Kim, Jeong Hyun Ha, Ji-Ung Park
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/41156ac7718940f690f028338fcefc8a
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spelling	oai:doaj.org-article:41156ac7718940f690f028338fcefc8a2021-12-02T13:35:03ZA selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model10.1038/s41598-021-84982-42045-2322https://doaj.org/article/41156ac7718940f690f028338fcefc8a2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84982-4https://doaj.org/toc/2045-2322Abstract Keloids, tumor-like lesions that result from excessive scar formation, have no definitive treatment modality. Activation of c-mesenchymal-epithelial transition factor (c-Met) promotes cell proliferation and survival. Selective c-Met inhibitors, such as PHA-665752, may attenuate the activity of keloid fibroblasts and reduce keloid formation. Here, we aimed to evaluate the effect of PHA-665752, a second-generation selective small-molecule inhibitor of c-Met, on human keloid fibroblasts in vitro and in a mouse model. We performed in vitro cytotoxicity assays, scratch tests, western blotting, and immunofluorescence on human keloid fibroblasts. We also injected human fibroblasts into severe combined immunodeficient mice and measured the degree of nodule formation and skin histologic characteristics. We found that keloid fibroblast migration was inhibited by PHA-665752. Inhibitor treatment was also associated with lower expression of members of the hepatocyte growth factor/c-Met pathway, and lower fibroblast activity and collagen synthesis. In the in vivo experiments, PHA-665752—treated mice had lower nodule volumes and weights, accompanied by less inflammatory cell infiltration and collagen deposition, than those in control mice. These findings showed that although an in vivo model may not accurately represent the pathophysiology of human keloid development, PHA-665752 suppressed keloid fibroblast activity by inhibiting the c-Met—related tyrosine kinase pathway.Min-Ha ChoiJinhyun KimJeong Hyun HaJi-Ung ParkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Min-Ha Choi Jinhyun Kim Jeong Hyun Ha Ji-Ung Park A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model
description	Abstract Keloids, tumor-like lesions that result from excessive scar formation, have no definitive treatment modality. Activation of c-mesenchymal-epithelial transition factor (c-Met) promotes cell proliferation and survival. Selective c-Met inhibitors, such as PHA-665752, may attenuate the activity of keloid fibroblasts and reduce keloid formation. Here, we aimed to evaluate the effect of PHA-665752, a second-generation selective small-molecule inhibitor of c-Met, on human keloid fibroblasts in vitro and in a mouse model. We performed in vitro cytotoxicity assays, scratch tests, western blotting, and immunofluorescence on human keloid fibroblasts. We also injected human fibroblasts into severe combined immunodeficient mice and measured the degree of nodule formation and skin histologic characteristics. We found that keloid fibroblast migration was inhibited by PHA-665752. Inhibitor treatment was also associated with lower expression of members of the hepatocyte growth factor/c-Met pathway, and lower fibroblast activity and collagen synthesis. In the in vivo experiments, PHA-665752—treated mice had lower nodule volumes and weights, accompanied by less inflammatory cell infiltration and collagen deposition, than those in control mice. These findings showed that although an in vivo model may not accurately represent the pathophysiology of human keloid development, PHA-665752 suppressed keloid fibroblast activity by inhibiting the c-Met—related tyrosine kinase pathway.
format	article
author	Min-Ha Choi Jinhyun Kim Jeong Hyun Ha Ji-Ung Park
author_facet	Min-Ha Choi Jinhyun Kim Jeong Hyun Ha Ji-Ung Park
author_sort	Min-Ha Choi
title	A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model
title_short	A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model
title_full	A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model
title_fullStr	A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model
title_full_unstemmed	A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model
title_sort	selective small-molecule inhibitor of c-met suppresses keloid fibroblast growth in vitro and in a mouse model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/41156ac7718940f690f028338fcefc8a
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A selective small-molecule inhibitor of c-Met suppresses keloid fibroblast growth in vitro and in a mouse model

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