Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK.
Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK.
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胃泌素抑制涉及 EGR1、AE2 和 P-ERK 的新型病理性结肠癌信号通路
DOI：
10.1007/s00109-011-0851-2
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Fu GH
中科院分区：
文献类型：
--
作者：
Song LJ;Liu RJ;Zeng Z;Alper SL;Cui HJ;Lu Y;Zheng L;Yan ZW;Fu GH
人阴离子交换器2（AE 2）是调节细胞内pH和细胞体积的质膜蛋白。AE 2有助于正常结肠和其他上皮组织中氯化物和碳酸氢盐的跨上皮转运。我们现在报道，AE 2在结肠癌细胞中的过表达与核增殖标记物Ki 67的表达相关。对24例早期结肠癌和33例管状腺癌患者的生存分析表明，AE 2的表达与不良预后相关。细胞和分子实验表明，AE 2的表达促进结肠癌细胞的增殖。此外，我们发现转录因子EGR 1是AE 2上调的基础，并且AE 2在结肠癌细胞的细胞质中隔离p16 INK 4a（P16）。胞浆P16增强ERK磷酸化，促进结肠癌细胞增殖。胃泌素通过抑制EGR 1和AE 2的表达以及阻断ERK磷酸化来抑制结肠癌细胞的增殖。总之，我们的数据描述了一种新的EGR 1/AE 2/P16/P-ERK信号通路在结肠癌的发生，与病理预后和新的治疗方法的影响。
Human anion exchanger 2 (AE2) is a plasma membrane protein that regulates intracellular pH and cell volume. AE2 contributes to transepithelial transport of chloride and bicarbonate in normal colon and other epithelial tissues. We now report that AE2 overexpression in colon cancer cells is correlated with expression of the nuclear proliferation marker, Ki67. Survival analysis of 24 patients with colon cancer in early stage or 33 patients with tubular adenocarcinoma demonstrated that expression of AE2 is correlated with poor prognosis. Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells. Cytoplasmic P16 enhanced ERK phosphorylation and promoted proliferation of colon cancer cells. Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. Taken together, our data describe a novel EGR1/AE2/P16/P-ERK signaling pathway in colon carcinogenesis, with implications for pathologic prognosis and for novel therapeutic approaches.