Abstract 4286: Hepatocyte growth factor-mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells.

Gastric cancer cells secrete a variety of pro-angiogenic molecules, including IL-8 and VEGF. However, factors regulating the expression of pro-angiogenic genes for gastric cancer remain largely undefined. We investigated the role of HGF-induced activation of GRP and Ets-1 transcription factor in expression of the pro-angioigenic factor, IL-8. The genes associated with angiogenesis induced by HGF were screened using cDNA microarray technology in two gastric cancer cell lines (NUGC-3 and MKN-28). First, GRP RNA and protein were confirmed to be up-regulated. Then, expression of GRP, Ets-1, and IL-8 were further estimated by Western blot analysis. A role for Ets-1 in HGF-induced up-regulation of IL-8 was determined by knockdown of Ets-1 with Ets-1 sh-RNA and a chromatin immune precipitation assay. The levels of GRP, Ets-1, and IL-8 were up-regulated in cells treated with HGF in a dose-dependent manner. HGF-induced expression of Ets-1 and IL-8 was increased more by GRP treatment, and inhibited by pre-treatment with an ERK 1/2 inhibitor (PD098059). HGF-induced up-regulation of IL-8 was repressed by Ets-1 knockdown. HGF enhanced the binding activity of Ets-1 to the IL-8 promoter in control cells, but not in the Ets-1 shRNA cells. We confirmed the functional role of HGF-induced Ets-1 in activation of the IL-8 promoter by the reporter gene assay. Down-regulation of IL-8 also decreased in vitro cell invasion. In conclusion, HGF mediated the GRP induction of IL-8 expression through Ets-1, which thus might serve as a promising target for gastric cancer therapy. Key words: HGF, GRP, Ets-1, IL-8 Citation Format: Sung Ae Koh, Kyung Hee Lee, Eun Young Choi, Min Kyung Kim, Byung Ik Jang, Se Won Kim, Sang Woon Kim, Sun Kyo Song, Jae Ryong Kim. Hepatocyte growth factor-mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2013-4286