Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells

Abstract Deficiency of p53 in cancer cells activates the transformation of normal tissue fibroblasts into carcinoma-associated fibroblasts; this promotes tumor progression through a variety of mechanisms in the tumor microenvironment. The role of autophagy in carcinoma-associated fibroblasts in tumo...

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Autores principales:	Takanori Inoue, Yoshito Hayashi, Yoshiki Tsujii, Shunsuke Yoshii, Akihiko Sakatani, Keiichi Kimura, Ryotaro Uema, Minoru Kato, Hirotsugu Saiki, Shinichiro Shinzaki, Hideki Iijima, Tetsuo Takehara
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/48df2cbf95cf44b7bd7c9b24f8fb0af2
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spelling	oai:doaj.org-article:48df2cbf95cf44b7bd7c9b24f8fb0af22021-12-02T18:51:28ZSuppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells10.1038/s41598-021-98865-12045-2322https://doaj.org/article/48df2cbf95cf44b7bd7c9b24f8fb0af22021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98865-1https://doaj.org/toc/2045-2322Abstract Deficiency of p53 in cancer cells activates the transformation of normal tissue fibroblasts into carcinoma-associated fibroblasts; this promotes tumor progression through a variety of mechanisms in the tumor microenvironment. The role of autophagy in carcinoma-associated fibroblasts in tumor progression has not been elucidated. We aimed to clarify the significance of autophagy in fibroblasts, focusing on the TP53 status in co-cultured human colorectal cancer cell lines (TP53-wild-type colon cancer, HCT116; TP53-mutant colon cancer, HT29; fibroblast, CCD-18Co) in vitro. Autophagy in fibroblasts was significantly suppressed in association with ACTA2, CXCL12, TGFβ1, VEGFA, FGF2, and PDGFRA mRNA levels, when co-cultured with p53-deficient HCT116 sh p53 cells. Exosomes isolated from the culture media of HCT116 sh p53 cells significantly suppressed autophagy in fibroblasts via inhibition of ATG2B. Exosomes derived from TP53-mutant HT29 cells also suppressed autophagy in fibroblasts. miR-4534, extracted from the exosomes of HCT116 sh p53 cells, suppressed ATG2B in fibroblasts. In conclusion, a loss of p53 function in colon cancer cells promotes the activation of surrounding fibroblasts through the suppression of autophagy. Exosomal miRNAs derived from cancer cells may play a pivotal role in the suppression of autophagy.Takanori InoueYoshito HayashiYoshiki TsujiiShunsuke YoshiiAkihiko SakataniKeiichi KimuraRyotaro UemaMinoru KatoHirotsugu SaikiShinichiro ShinzakiHideki IijimaTetsuo TakeharaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takanori Inoue Yoshito Hayashi Yoshiki Tsujii Shunsuke Yoshii Akihiko Sakatani Keiichi Kimura Ryotaro Uema Minoru Kato Hirotsugu Saiki Shinichiro Shinzaki Hideki Iijima Tetsuo Takehara Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
description	Abstract Deficiency of p53 in cancer cells activates the transformation of normal tissue fibroblasts into carcinoma-associated fibroblasts; this promotes tumor progression through a variety of mechanisms in the tumor microenvironment. The role of autophagy in carcinoma-associated fibroblasts in tumor progression has not been elucidated. We aimed to clarify the significance of autophagy in fibroblasts, focusing on the TP53 status in co-cultured human colorectal cancer cell lines (TP53-wild-type colon cancer, HCT116; TP53-mutant colon cancer, HT29; fibroblast, CCD-18Co) in vitro. Autophagy in fibroblasts was significantly suppressed in association with ACTA2, CXCL12, TGFβ1, VEGFA, FGF2, and PDGFRA mRNA levels, when co-cultured with p53-deficient HCT116 sh p53 cells. Exosomes isolated from the culture media of HCT116 sh p53 cells significantly suppressed autophagy in fibroblasts via inhibition of ATG2B. Exosomes derived from TP53-mutant HT29 cells also suppressed autophagy in fibroblasts. miR-4534, extracted from the exosomes of HCT116 sh p53 cells, suppressed ATG2B in fibroblasts. In conclusion, a loss of p53 function in colon cancer cells promotes the activation of surrounding fibroblasts through the suppression of autophagy. Exosomal miRNAs derived from cancer cells may play a pivotal role in the suppression of autophagy.
format	article
author	Takanori Inoue Yoshito Hayashi Yoshiki Tsujii Shunsuke Yoshii Akihiko Sakatani Keiichi Kimura Ryotaro Uema Minoru Kato Hirotsugu Saiki Shinichiro Shinzaki Hideki Iijima Tetsuo Takehara
author_facet	Takanori Inoue Yoshito Hayashi Yoshiki Tsujii Shunsuke Yoshii Akihiko Sakatani Keiichi Kimura Ryotaro Uema Minoru Kato Hirotsugu Saiki Shinichiro Shinzaki Hideki Iijima Tetsuo Takehara
author_sort	Takanori Inoue
title	Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
title_short	Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
title_full	Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
title_fullStr	Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
title_full_unstemmed	Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
title_sort	suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/48df2cbf95cf44b7bd7c9b24f8fb0af2
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Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells

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