Epigenetic modulation and repression of miR-200b by cancer-associated fibroblasts contribute to cancer invasion and peritoneal dissemination in gastric cancer

• Published in: Carcinogenesis (New York) Vol. 36; no. 1; pp. 133 - 141
• Main Authors: Kurashige, Junji, Mima, Kosuke, Sawada, Genta, Takahashi, Yusuke, Eguchi, Hidetoshi, Sugimachi, Keishi, Mori, Masaki, Yanagihara, Kazuyoshi, Yashiro, Masakazu, Hirakawa, Kosei, Baba, Hideo, Mimori, Koshi
• Format: Journal Article
• Language: English
• Published: England 01.01.2015
• Subjects: Adenocarcinoma, Scirrhous - genetics; Adenocarcinoma, Scirrhous - metabolism; Adenocarcinoma, Scirrhous - pathology; Animals; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; CpG Islands; DNA Methylation; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Invasiveness; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - secondary; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgu232

Cancer-associated fibroblasts (CAFs) have recently been linked to the invasion and metastasis of gastric cancer. In addition, the microRNA (miR)-200 family plays a central role in the regulation of the epithelial-mesenchymal transition process during cancer metastasis, and aberrant DNA methylation is one of the key mechanisms underlying regulation of the miR-200 family. In this study, we clarified whether epigenetic changes of miR-200b by CAFs stimulate cancer invasion and peritoneal dissemination in gastric cancer. We evaluated the relationship between miR-200b and CAFs using a coculture model. In addition, we established a peritoneal metastasis mouse model and investigated the expression and methylation status of miR-200b. We also investigated the expression and methylation status of miR-200b and CAFs expression in primary gastric cancer samples. CAFs (CAF-37 and CAF-50) contributed to epigenetic changes of miR-200b, reduced miR-200b expression and promoted tumor invasion and migration in NUGC3 and OCUM-2M cells in coculture. In the model mice, epigenetic changes of miR-200b were observed in the inoculated high-frequency peritoneal dissemination cells. In the 173 gastric cancer samples, the low miR-200b expression group demonstrated a significantly poorer prognosis compared with the high miR-200b expression group and was associated with peritoneal metastasis. In addition, downregulation of miR-200b in cancer cells was significantly correlated with alpha-smooth muscle actin expression. Our data provide evidence that CAFs reduce miR-200b expression and promote tumor invasion through epigenetic changes of miR-200b in gastric cancer. Thus, CAFs might be a therapeutic target for inhibition of gastric cancer.