期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1868, 期 3, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2020.118920
关键词
AGR2; Endoplasmic reticulum; Lung cancer; Tumour microenvironment; p21CIP1
资金
- Site de recherche integree sur le cancer de Bordeaux (SIRIC Brio)
- Ligue contre le Cancer (Comite Charente)
- Fondation ARC pour la recherche sur le cancer
- Institut National du Cancer (INCa)
- Fondation pour la Recherche Medicale (FRM, equipe labellisee)
- Agence Nationale de la Recherche (ANR)
AGR2 acts as a growth factor in the tumor microenvironment by enhancing tumor cell growth through repression of p21(CIP1). Targeting the eAGR2/p21(CIP1) signaling pathway may be a potential therapeutic strategy to inhibit tumor growth.
The human Anterior GRadient 2 (AGR2) protein is an Endoplasmic Reticulum (ER)-resident protein which belongs to the Protein-Disulfide Isomerase (PDI) superfamily and is involved to productive protein folding in the ER. As such AGR2, often found overexpressed in adenocarcinomas, contributes to tumour development by enhancing ER proteostasis. We previously demonstrated that AGR2 is secreted (extracellular AGR2 (eAGR2)) in the tumour microenvironment and plays extracellular roles independent of its ER functions. Herein, we show that eAGR2 triggers cell proliferation and characterize the underlying molecular mechanisms. We demonstrate that eAGR2 enhances tumour cell growth by repressing the tumour suppressor p21(CIP1). Our findings shed light on a novel mechanism through which eAGR2 behaves as a growth factor in the tumour microenvironment, independently of its ER function, thus promoting tumour cell growth through repression of p21(CIP1). Our results provide a rationale for targeting eAGR2/p21(CIP1)-based signalling as a potential therapeutic target to impede tumour growth.
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