Proton-sensing GPCR-YAP Signalling Promotes Cancer-associated Fibroblast Activation of Mesenchymal Stem Cells

被引：38

作者：

Zhu, Hongyi ^{[1
]}

Guo, Shangchun ^{[2
]}

Zhang, Yuelei ^{[1
]}

Yin, Junhui ^{[2
]}

Yin, Wenjing ^{[1
]}

Tao, Shicong ^{[1
]}

Wang, Yang ^{[2
]}

Zhang, Changqing ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Orthopaed Surg, Shanghai 200233, Peoples R China

[2] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Inst Microsurg Extrem, Shanghai 200233, Peoples R China

来源：

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES | 2016年 / 12卷 / 04期

基金：

中国国家自然科学基金;

关键词：

pH; YAP; proton-sensing; GPCR; cancer; fibroblast; TUMOR-GROWTH; PROLIFERATION; INVOLVEMENT; TRANSITION; EXPRESSION; TDAG8; BETA;

D O I：

10.7150/ijbs.13688

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The pHs of extracellular fluids (ECFs) in normal tissues are commonly maintained at 7.35 to 7.45. The acidification of the ECF is one of the major characteristics of tumour microenvironment. In this study, we report that decreased extracellular pH promotes the transformation of mesenchymal stem cells (MSCs) into cancer-associated fibroblasts (CAFs), termed CAF activation. Furthermore, we demonstrate that GPR68, a proton-sensing G-protein-coupled receptor (GPCR), is required for the pH-dependent regulation of the differentiation of MSCs into CAFs. We then identify Yes-associated protein 1 (YAP) as a downstream effector of GPR68 for CAF activation. Finally, we show that knockdown of GPR68 in MSCs can prevent the CAF activation under cancer microenvironment. Systemic transplantation of GPR68-silenced MSCs suppresses in-situ tumour growth and prolong life span after cancer graft.

引用

页码：389 / 396

页数：8

共 27 条

[1] Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment [J].

Augsten, Martin .

FRONTIERS IN ONCOLOGY, 2014, 4

[2] TGF-beta in CAF-mediated tumor growth and metastasis [J].

Calon, A. ;

Tauriello, D. V. F. ;

Batlle, E. .

SEMINARS IN CANCER BIOLOGY, 2014, 25 :15-22

[3] Gene expression signature of fibroblast serum response predicts human cancer progression: Similarities between tumors and wounds [J].

Chang, HY ;

Sneddon, JB ;

Alizadeh, AA ;

Sood, R ;

West, RB ;

Montgomery, K ;

Chi, JT ;

van de Rijn, M ;

Botstein, D ;

Brown, PO .

PLOS BIOLOGY, 2004, 2 (02) :206-214

[4] Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway [J].

Chen, Aishe ;

Dong, Lixue ;

Leffler, Nancy R. ;

Asch, Adam S. ;

Witte, Owen N. ;

Yang, Li V. .

PLOS ONE, 2011, 6 (11)

[5]

Cirri P, 2011, AM J CANCER RES, V1, P482

[6] Involvement of proton-sensing receptor TDAG8 in the anti-inflammatory actions of dexamethasone in peritoneal macrophages [J].

He, Xiao-dong ;

Tobo, Masayuki ;

Mogi, Chihiro ;

Nakakura, Takashi ;

Komachi, Mayumi ;

Murata, Naoya ;

Takano, Mutsumi ;

Tomura, Hideaki ;

Sato, Koichi ;

Okajima, Fumikazu .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2011, 415 (04) :627-631

[7]

Ishii G, 2015, ADV DRUG DELIVERY RE

[8] The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts [J].

Kuchnio, Anna ;

Moens, Stijn ;

Bruning, Ulrike ;

Kuchnio, Karol ;

Cruys, Bert ;

Thienpont, Bernard ;

Broux, Michael ;

Ungureanu, Andreea Alexandra ;

de Oliveira, Rodrigo Leite ;

Bruyere, Francoise ;

Cuervo, Henar ;

Manderveld, Ann ;

Carton, An ;

Hernandez-Femaud, Juan Ramon ;

Zanivan, Sara ;

Bartic, Carmen ;

Foidart, Jean-Michel ;

Noel, Agnes ;

Vinckier, Stefan ;

Lambrechts, Diether ;

Dewerchin, Mieke ;

Mazzone, Massimiliano ;

Carmeliet, Peter .

CELL REPORTS, 2015, 12 (06) :992-1005

[9] Acidosis Decreases c-Myc Oncogene Expression in Human Lymphoma Cells: A Role for the Proton-Sensing G Protein-Coupled Receptor TDAG8 [J].

Li, Zhigang ;

Dong, Lixue ;

Dean, Eric ;

Yang, Li V. .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2013, 14 (10) :20236-20255

[10] Proton-sensing G-protein-coupled receptors [J].

Ludwig, MG ;

Vanek, M ;

Guerini, D ;

Gasser, JA ;

Jones, CE ;

Junker, U ;

Hofstetter, H ;

Wolf, RM ;

Seuwen, K .

NATURE, 2003, 425 (6953) :93-98

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