Carcinogenesis Advance Access first published online on November 16, 2007
This version published online on November 27, 2007
Carcinogenesis, doi:10.1093/carcin/bgm250
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REG I
Protein Mediates an Anti-apoptotic Effect of STAT3 Signaling in Gastric Cancer Cells
* Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Correspondence: Hirokazu Fukui, M.D., Ph.D., Department of Surgical and Molecular, Pathology, Dokkyo University School of Medicine, 880 Kitakobayshi, Mibu, Shimotsuga, Tochigi, 321-0293 Japan., Phone: +81-282-87-2130; FAX: +81-282-86-1681, E-mail: h-fukui{at}dokkyomed.ac.jp
Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) I
protein, an interleukin (IL)-6-inducible gene, is suggested to be involved in the gastritis-gastric cancer sequence. We investigated involvement of IL-6/STAT3 signaling in REG I protein expression, and examined whether REG I protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG I protein expression were examined using a STAT3 small interfering RNA (siRNA) system in gastric cancer cells. The element responsible for IL-6-induced REG I promoter activation was determined by promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced-REG I protein were examined by TUNEL and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated STAT3 (p-STAT3) and REG I protein. IL-6 treatment enhanced the expression of REG I protein through STAT3 activation in gastric cancer cells. The IL-6-responsive element was determined to lie in the sequence from –142 to –134 of the REG I promoter region. REG I protein mediated the anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL expression. The expression of REG I protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG I protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.
Grant Support: This work was supported in part by Grants-in-aid for Scientific Research 17590635 from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and Grants-in-aid for Research on Measures for Intractable Diseases, and Research on Advanced Medical Technology from the Ministry of Health, Labor, and Welfare, Japan.
This paper was published under the Open Access model, but has now been placed under subscription control.
Received July 31, 2007; revised October 3, 2007; accepted November 2, 2007.