Limits...
Combined Secretomics and Transcriptomics Revealed Cancer-Derived GDF15 is Involved in Diffuse-Type Gastric Cancer Progression and Fibroblast Activation.

Ishige T, Nishimura M, Satoh M, Fujimoto M, Fukuyo M, Semba T, Kado S, Tsuchida S, Sawai S, Matsushita K, Togawa A, Matsubara H, Kaneda A, Nomura F - Sci Rep (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

GDF15 protein expression of gastric cancer cell lines and tissues.(A) GDF15 protein expression of the six gastric cancer cell lines. KATO-III, OCUM-1, NUGC-4, and MKN-45 belonged to the diffuse-type and MKN-7 and MKN-74 represented the intestinal-type. (B) GDF15 protein expression of gastric cancer tissues. Left, gastritis (benign); center, intestinal-type gastric cancer (malignant); right, diffuse-type gastric cancer (signet ring cell carcinoma, malignant). Bars indicate 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4759594&req=5

f3: GDF15 protein expression of gastric cancer cell lines and tissues.(A) GDF15 protein expression of the six gastric cancer cell lines. KATO-III, OCUM-1, NUGC-4, and MKN-45 belonged to the diffuse-type and MKN-7 and MKN-74 represented the intestinal-type. (B) GDF15 protein expression of gastric cancer tissues. Left, gastritis (benign); center, intestinal-type gastric cancer (malignant); right, diffuse-type gastric cancer (signet ring cell carcinoma, malignant). Bars indicate 100 μm.

Mentions: To search for the distribution and the specificity of protein expression in various normal tissues, 15 DGC related genes were analyzed using two proteome databases, Human Protein Atlas13 and Human Proteome Map14. We selected GDF15 for further analysis by the following criteria: 1) negative to low expression in adult tissues and 2) high expression in fetal tissues (Supplementary Figures 2 and 3). Immunoblotting of the six gastric cancer cell lines showed higher GDF15 protein expression of DGC cell lines (KATO-III, OCUM-1, NUGC-4, and MKN-45) than that of IGC cell lines (MKN-7 and MKN-74) (Fig. 3A). Immunohistochemistry also revealed high expression in DGC (signet ring cell carcinoma) (Fig. 3B). In addition, reanalyzing previously reported microarray data of DGC and IGC tissues (GSE22377), mRNA expression of GDF15 was 1.6-fold higher in DGC tissues (Welch’s T-test, P = 0.035, data not shown)15.


Combined Secretomics and Transcriptomics Revealed Cancer-Derived GDF15 is Involved in Diffuse-Type Gastric Cancer Progression and Fibroblast Activation.

Ishige T, Nishimura M, Satoh M, Fujimoto M, Fukuyo M, Semba T, Kado S, Tsuchida S, Sawai S, Matsushita K, Togawa A, Matsubara H, Kaneda A, Nomura F - Sci Rep (2016)

GDF15 protein expression of gastric cancer cell lines and tissues.(A) GDF15 protein expression of the six gastric cancer cell lines. KATO-III, OCUM-1, NUGC-4, and MKN-45 belonged to the diffuse-type and MKN-7 and MKN-74 represented the intestinal-type. (B) GDF15 protein expression of gastric cancer tissues. Left, gastritis (benign); center, intestinal-type gastric cancer (malignant); right, diffuse-type gastric cancer (signet ring cell carcinoma, malignant). Bars indicate 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759594&req=5

f3: GDF15 protein expression of gastric cancer cell lines and tissues.(A) GDF15 protein expression of the six gastric cancer cell lines. KATO-III, OCUM-1, NUGC-4, and MKN-45 belonged to the diffuse-type and MKN-7 and MKN-74 represented the intestinal-type. (B) GDF15 protein expression of gastric cancer tissues. Left, gastritis (benign); center, intestinal-type gastric cancer (malignant); right, diffuse-type gastric cancer (signet ring cell carcinoma, malignant). Bars indicate 100 μm.
Mentions: To search for the distribution and the specificity of protein expression in various normal tissues, 15 DGC related genes were analyzed using two proteome databases, Human Protein Atlas13 and Human Proteome Map14. We selected GDF15 for further analysis by the following criteria: 1) negative to low expression in adult tissues and 2) high expression in fetal tissues (Supplementary Figures 2 and 3). Immunoblotting of the six gastric cancer cell lines showed higher GDF15 protein expression of DGC cell lines (KATO-III, OCUM-1, NUGC-4, and MKN-45) than that of IGC cell lines (MKN-7 and MKN-74) (Fig. 3A). Immunohistochemistry also revealed high expression in DGC (signet ring cell carcinoma) (Fig. 3B). In addition, reanalyzing previously reported microarray data of DGC and IGC tissues (GSE22377), mRNA expression of GDF15 was 1.6-fold higher in DGC tissues (Welch’s T-test, P = 0.035, data not shown)15.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.

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.

No MeSH data available.


Related in: MedlinePlus