The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

Saiki, Hirotsugu; Hayashi, Yoshito; Yoshii, Shunsuke; Kimura, Eiji; Nakagawa, Kentaro; Kato, Minoru; Uema, Ryotaro; Inoue, Takanori; Sakatani, Akihiko; Yoshihara, Takeo; Tsujii, Yoshiki; Shinzaki, Shinichiro; Iijima, Hideki; Takehara, Tetsuo

doi:https://doi.org/10.3892/ijo.2023.5587

The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

Saiki, Hirotsugu; Hayashi, Yoshito; Yoshii, Shunsuke et al.

International Journal of Oncology, 2023, 63(6), 139

Number of Access:1,844（2025-09-06 05:36 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/93375

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Title	The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells
Creator	CreatorName Saiki, Hirotsugu
	NRID 1000080647123 1000080647123 researchmap permalink y-h y-h Scopus Author ID 35219993200 35219993200 CreatorName Hayashi, Yoshito
	NRID 1000090771882 1000090771882 CreatorName Yoshii, Shunsuke
	CreatorName Kimura, Eiji
	CreatorName Nakagawa, Kentaro
	NRID 1000080939249 1000080939249 researchmap permalink mk-37 mk-37 CreatorName Kato, Minoru
	NRID 1000030939161 1000030939161 researchmap permalink ryotarouema ryotarouema CreatorName Uema, Ryotaro
	CreatorName Inoue, Takanori
	CreatorName Sakatani, Akihiko
	NRID 1000020814601 1000020814601 researchmap permalink ty_gh ty_gh CreatorName Yoshihara, Takeo
	NRID 1000080795170 1000080795170 researchmap permalink yhcks yhcks Scopus Author ID 57192176408 57192176408 CreatorName Tsujii, Yoshiki
	NRID 1000060546860 1000060546860 CreatorName Shinzaki, Shinichiro
	NRID 1000090444520 1000090444520 researchmap permalink _0719 _0719 CreatorName Iijima, Hideki
	NRID 1000070335355 1000070335355 researchmap permalink takeharatetsuo takeharatetsuo Scopus Author ID 7103332258 7103332258 CreatorName Takehara, Tetsuo
Subject	cancer-associated fibroblasts
	colonic neoplasms
	exosomes
	microRNAs
	tumor microenvironment
Description	Saiki H., Hayashi Y., Yoshii S., et al. The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells. International Journal of Oncology 63, 139 (2023); https://doi.org/10.3892/ijo.2023.5587.
Abstract	Cancer-associated fibroblasts (CAFs) are pivotal in tumor progression. TP53-deficiency in cancer cells is associated with robust stromal activation. The apelin-apelin receptor (APJ) system has been implicated in suppressing fibroblast-to-myofibroblast transition in non-neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin-APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53-wild colon cancer, HCT116, and Caco-2; TP53-mutant colon cancer, SW480, and DLD-1; and colon fibroblasts, CCD-18Co), resected human tissue samples of colorectal cancers, and immune-deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co-cultured with p53-suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ-suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast-like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma- and Mad-related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ-suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR-5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell-derived exosomes induced CAF-like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.
Publisher	Spandidos Publications
Source Title	International Journal of Oncology
Volume (Issue)	63(6)
Page	139
Date of Issued	2023-10-18
Language	English
Handle URL	https://hdl.handle.net/11094/93375
PISSN	10196439
eISSN	17912423
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.3892/ijo.2023.5587
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	International Journal of Oncology. 2023, 63(6), p. 139
DC.title	The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells
DC.creator	Saiki, Hirotsugu
	Hayashi, Yoshito
	Yoshii, Shunsuke
	Kimura, Eiji
	Nakagawa, Kentaro
	Kato, Minoru
	Uema, Ryotaro
	Inoue, Takanori
	Sakatani, Akihiko
	Yoshihara, Takeo
	Tsujii, Yoshiki
	Shinzaki, Shinichiro
	Iijima, Hideki
	Takehara, Tetsuo
DC.publisher	Spandidos Publications
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2023-10-18
DC.identifier	https://doi.org/10.3892/ijo.2023.5587
DC.subject	cancer-associated fibroblasts
	colonic neoplasms
	exosomes
	microRNAs
	tumor microenvironment
DC.description	Saiki H., Hayashi Y., Yoshii S., et al. The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells. International Journal of Oncology 63, 139 (2023); https://doi.org/10.3892/ijo.2023.5587.
DCTERMS.abstract	Cancer-associated fibroblasts (CAFs) are pivotal in tumor progression. TP53-deficiency in cancer cells is associated with robust stromal activation. The apelin-apelin receptor (APJ) system has been implicated in suppressing fibroblast-to-myofibroblast transition in non-neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin-APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53-wild colon cancer, HCT116, and Caco-2; TP53-mutant colon cancer, SW480, and DLD-1; and colon fibroblasts, CCD-18Co), resected human tissue samples of colorectal cancers, and immune-deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co-cultured with p53-suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ-suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast-like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma- and Mad-related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ-suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR-5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell-derived exosomes induced CAF-like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	93375
citation_title	The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells
citation_author	Saiki, Hirotsugu
	Hayashi, Yoshito
	Yoshii, Shunsuke
	Kimura, Eiji
	Nakagawa, Kentaro
	Kato, Minoru
	Uema, Ryotaro
	Inoue, Takanori
	Sakatani, Akihiko
	Yoshihara, Takeo
	Tsujii, Yoshiki
	Shinzaki, Shinichiro
	Iijima, Hideki
	Takehara, Tetsuo
citation_publisher	Spandidos Publications
citation_language	English
citation_date	2023-10-18
citation_journal_title	International Journal of Oncology
citation_volume	63
citation_issue	6
citation_firstpage	139
citation_doi	https://doi.org/10.3892/ijo.2023.5587
citation_public_url	https://hdl.handle.net/11094/93375

The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

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