REG Iα protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells
REG Iα protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells
复制标题
DOI：
10.1093/carcin/bgm250
复制
发表时间：
2008-01-01
期刊：
影响因子：
4.7
通讯作者：
Fujimori, Takahiro
中科院分区：
文献类型：
--
作者：
Sekikawa, Akira;Fukui, Hirokazu;Fujimori, Takahiro
信号转导和转录激活子3(STAT3)信号在炎症相关的癌变过程中发挥作用。再生基因(Reg)Iα蛋白是一种白介素6(IL-6)诱导基因，被认为参与了胃炎-胃癌的发病过程。我们研究了IL-6/STAT3信号在Reg Iα蛋白表达中的作用，并检测了Reg Iα蛋白是否介导了STAT3信号在胃癌细胞中的抗凋亡作用。利用STAT3小干扰RNA系统检测IL-6/STAT3信号转导对胃癌细胞Reg Iα蛋白表达的影响。通过启动子缺失分析确定了IL-6诱导的Reg Iα启动子激活的元件。采用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸酶缺口末端标记法和半胱氨酸天冬氨酸氨基转移酶(Caspase)法检测STAT3信号及其诱导的Reg Iα蛋白在体外的抗细胞凋亡作用。采用免疫组织化学方法检测人胃癌组织中磷酸化信号转导和转录激活因子3(p-STAT3)和Reg Iα蛋白的表达。IL-6通过激活STAT3促进胃癌细胞中Reg Iα蛋白的表达。IL-6反应元件位于Reg Iα启动子区-142至-134的序列中。Reg Iα蛋白通过促进Akt活化、Bad磷酸化和Bclxl表达而介导STAT3信号转导胃癌细胞的抗凋亡作用。胃癌组织中Reg Iα蛋白的表达与p-STAT3的表达呈正相关。在STAT3激活的胃肿瘤发生过程中，Reg Iα蛋白可能在抗细胞凋亡中起关键作用。
Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) I alpha 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 alpha protein expression and examined whether REG I alpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG I alpha protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG I alpha promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG I alpha 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 alpha protein. IL-6 treatment enhanced the expression of REG I alpha 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 alpha promoter region. REG I alpha 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 alpha protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG I alpha protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.