Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.
Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.
复制标题
IL-1beta/Akt/RARα/Akt 信号传导的正反馈环介导 RARα 在胃癌中的致癌特性。
DOI：
10.18632/oncotarget.14267
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发表时间：
2017-01-24
期刊：
影响因子：
--
通讯作者：
Shen DY
中科院分区：
文献类型：
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作者：
Ren HY;Liu F;Huang GL;Liu Y;Shen JX;Zhou P;Liu WM;Shen DY
视黄酸受体α（RARα）的异常表达和功能已被报道与包括急性早幼粒细胞白血病和肝细胞癌在内的多种癌症有关。然而RARα在胃癌中的作用及其机制尚不清楚。RARα在人胃癌组织和细胞系中的表达频繁升高，其过表达与胃癌患者的肿瘤大小、淋巴结转移和临床分期密切相关。RARα表达与病理分化程度有关。在功能上，RARα基因敲低可抑制胃癌细胞的增殖和转移，并增强胃癌细胞的药物敏感性。此外，RARα基因敲低可通过调节细胞增殖、细胞周期、侵袭和耐药相关蛋白如PCNA、CyclinB 1、CyclinD 2、CyclinE、p21、MMP 9和MDR 1的表达来抑制胃癌的进展。RARα在胃癌中的上述致癌特性与Akt信号通路的激活密切相关。IL-1β/Akt信号通路激活可诱导RARα的过度表达，提示IL-1β/Akt/RARα/Akt信号通路在胃癌中存在正反馈环。综上所述，我们证明RARα在GC中经常升高，并具有致癌特性。它可能是GC治疗的潜在分子靶点。
Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1β/Akt signaling activation, which suggested a positive feedback loop of IL-1β/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.