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

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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Main Authors: Takanori Inoue, Yoshito Hayashi, Yoshiki Tsujii, Shunsuke Yoshii, Akihiko Sakatani, Keiichi Kimura, Ryotaro Uema, Minoru Kato, Hirotsugu Saiki, Shinichiro Shinzaki, Hideki Iijima, Tetsuo Takehara
Format: article
Language:EN
Published: Nature Portfolio 2021
Subjects:
Medicine
R
Science
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Online Access:https://doaj.org/article/48df2cbf95cf44b7bd7c9b24f8fb0af2
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Summary: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.

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