Carcinogenesis Advance Access originally published online on November 16, 2007
Carcinogenesis 2008 29(1):76-83; 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 880 Kitakobayshi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
1 Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
* To whom correspondence should be addressed. Tel: +81 282 87 2130; Fax: +81 282 86 1681; Email: 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 the 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 system in gastric cancer cells. The element responsible for IL-6-induced REG I promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG I protein were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (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.
Abbreviations: ERK, extracellular signal-regulated protein kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; PCR, polymerase chain reaction; p-Akt, phospho-specific Akt; p-Bad, phospho-specific Bad; p-ERK, phospho-specific extracellular signal-regulated protein kinase; p-STAT3, phosphorylated signal transducer and activator of transcription 3; REG, regenerating gene; REG-R, regenerating gene receptor; siRNA, small interfering RNA; ssDNA, single-stranded DNA; STAT3, signal transducer and activator of transcription 3; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling
Received July 31, 2007; revised October 3, 2007; accepted November 2, 2007.