REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells.
Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) Ialpha 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 Ialpha protein expression and examined whether REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG Ialpha protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG Ialpha promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG Ialpha 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 Ialpha protein. IL-6 treatment enhanced the expression of REG Ialpha 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 Ialpha promoter region. REG Ialpha 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 Ialpha protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG Ialpha protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.
Sekikawa
Akira
A
Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine 880 Kitakobayshi, Mibu, Shimotsuga, Tochigi 321-0293, Japan.
Fukui
Hirokazu
H
Fujii
Shigehiko
S
Ichikawa
Kazuhito
K
Tomita
Shigeki
S
Imura
Johji
J
Chiba
Tsutomu
T
Fujimori
Takahiro
T
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007150:Immunohistochemistry; D051847:Lithostathine / Q000502:physiology*; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D017931:DNA Primers; D051847:Lithostathine; C497617:REG1A protein, human; D050796:STAT3 Transcription Factor