title: Agr2 mediates paracrine effects on stromal fibroblasts that promote invasion by gastric signet-ring carcinoma cells.
abstract: Agr2 is a disulfide isomerase residing in the endoplasmic reticulum (ER), which physiologically regulates protein folding and mediates resistance to ER stress. Agr2 is overexpressed in adenocarcinomas of various organs, where it participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides its normal localization in the ER, Agr2 is also found in the serum and urine of cancer patients, although the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated that extracellular Agr2 can activate stromal fibroblasts and promote fibroblast-associated cancer invasion in gastric signet-ring cell carcinoma (SRCC), where Agr2 is highly expressed. Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts coordinated the invasive behavior of fibroblasts and cancer cells. Our findings suggested that Agr2 drives progression of gastric SRCC by exerting paracrine effects on fibroblasts in the tumor microenvironment, acting also to increase the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects.
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan. Department of Otorhinolaryngology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Satoyoshi
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Aiba
authors.affiliation: Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Asaminami-ku, Hiroshima, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Division of Translational Research, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Cellular and Organ pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Cellular and Organ pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.affiliation: Department of Otorhinolaryngology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan. mastanak@med.akita-u.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D018279:Carcinoma, Signet Ring Cell / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009088:Mucoproteins / Q000096:biosynthesis / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins; D018384:Oxidative Stress / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C526445:Agr2 protein, mouse; D009088:Mucoproteins; D015513:Oncogene Proteins