Takayuki Ishige (Presenter)
Chiba University Hospital
Authorship: Takayuki Ishige (1), Motoi Nishimura (1), Mamoru Satoh (2), Kazuyuki Matsushita (1), Fumio Nomura (2)
(1) Division of Laboratory Medicine, Chiba University Hospital, Chiba, Japan (2) Division of Clinical Mass Spectrometry, Chiba University Hospital, Chiba, Japan
| Short Abstract The purpose of this study was to identify functional secreted molecules involved in diffuse-type gastric cancer progression. We integrated the secretomics of six gastric cancer cell lines and gene expression analysis of gastric cancer tissues with publicly available microarray data. This study revealed that GDF15 may be a novel functional secreted molecule for diffuse-type gastric cancer progression, possibly having important roles for cancer progression via the affecting fibroblast function, as well as TGF-ƒÀ. |
Long Abstract
Gastric cancer is classified into two subtypes, diffuse and intestinal. The diffuse-type gastric cancer has poorer prognosis, and the molecular pathology is not yet fully understood. The purpose of this study was to discover functional secreted molecules for diffuse-type gastric cancer progression.
We integrated the secretomics of six gastric cancer cell lines (four diffuse-types and two intestinal-types) and gene expression analysis of gastric cancer tissues with publicly available microarray data. Shotgun secretomics identified a total of 1,192 nonredundant proteins. Of these, 1,181/1,192 proteins (99%) were analyzed using gene expression analysis. We identified 51 genes being upregulated in gastric cancer tissues. Hierarchical clustering of these 51 genes in the six gastric cancer cell lines revealed characteristic gene expression differences between diffuse- and intestinal-types, and 15 genes were identified as diffuse-type gastric cancer related genes. Comparing with normal tissue distribution of protein expression, GDF15 was selected as a candidate owing to high expression only in fetal tissues. Protein expression of GDF15 was higher in diffuse-type gastric cancer cell lines and tissues. Serum levels of GDF15 were significant higher in diffuse-type gastric cancer patients as compared with healthy individuals and chronic gastritis patients, and positively correlated with wall invasion and lymph node metastasis. Because GDF15 is a member of the TGF-ƒÀ superfamily, we compared the effect of GDF15 and TGF-ƒÀ, which is one of the key mediators of fibroblast activation, on NIH3T3 fibroblast. As a result of transcriptomic analysis, the expression patterns of GDF15 and TGF-ƒÀ stimulation were similar. Notably, GDF15 enhanced proliferation and upregulated expression of extracellular matrix genes. These results indicate that GDF15 contributes to fibroblast activation.
In conclusion, this study revealed that GDF15 may be a novel functional secreted molecule for diffuse-type gastric cancer progression, possibly having important roles for cancer progression via the affecting fibroblast function, as well as TGF-ƒÀ.
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