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Possible Involvement of RUNX3 Silencing in the Peritoneal Metastases of Gastric Cancers

Authors' Affiliations: ¹ Surgery and Regenerative Medicine, Surgery and Physiology of Digestive System; ² Division of Gastroenterology, Graduate School of Internal Medicine, Kyoto Prefectural University of Medicine; and ³ Division of Gastroenterology and Hepatology, Graduate School of Internal Medicine, Kyoto University, Kyoto, Japan

Requests for reprints: Chouhei Sakakura, Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kawaramachi-dori, Kyoto 602, Japan. Phone: 81-75-251-5527; Fax: 81-75-251-5522; E-mail: sakakura{at}koto.kpu-m.ac.jp.

Purpose: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear. We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray.

Experimental Design and Results: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-ß (TGF-ß)–induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of 21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified 28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in the TGF-ß signaling pathway.

Conclusion: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.

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