title: Combined Secretomics and Transcriptomics Revealed Cancer-Derived GDF15 is Involved in Diffuse-Type Gastric Cancer Progression and Fibroblast Activation.
abstract: Gastric cancer is classified into two subtypes, diffuse and intestinal. The diffuse-type gastric cancer (DGC) has poorer prognosis, and the molecular pathology is not yet fully understood. The purpose of this study was to identify functional secreted molecules involved in DGC progression. We integrated the secretomics of six gastric cancer cell lines and gene expression analysis of gastric cancer tissues with publicly available microarray data. Hierarchical clustering revealed characteristic gene expression differences between diffuse- and intestinal-types. GDF15 was selected as a functional secreted molecule owing to high expression only in fetal tissues. Protein expression of GDF15 was higher in DGC cell lines and tissues. Serum levels of GDF15 were significant higher in DGC patients as compared with healthy individuals and chronic gastritis patients, and positively correlated with wall invasion and lymph node metastasis. In addition, the stimulation of GDF15 on NIH3T3 fibroblast enhanced proliferation and up-regulated expression of extracellular matrix genes, which were similar to TGF-β stimulation. These results indicate that GDF15 contributes to fibroblast activation. In conclusion, this study revealed that GDF15 may be a novel functional secreted molecule for DGC progression, possibly having important roles for cancer progression via the affecting fibroblast function, as well as TGF-β.
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishige
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.|Clinical Proteomics Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.|Clinical Proteomics Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukuyo
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Semba
authors.affiliation: Center for Analytical Instrumentation, Chiba University, Chiba, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kado
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.|Clinical Proteomics Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Tsuchida
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.|Clinical Proteomics Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Setsu
authors.initials: S
authors.lastname: Sawai
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.|Clinical Proteomics Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Department of Surgery, Toyo Municipal Hospital, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Togawa
authors.affiliation: Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneda
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.|Clinical Proteomics Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019295:Computational Biology; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D016212:Transforming Growth Factor beta