Glucose-derived AGEs promote migration and invasion of colorectal cancer by up-regulating Sp1 expression
Glucose-derived AGEs promote migration and invasion of colorectal cancer by up-regulating Sp1 expression
复制标题
葡萄糖源性AGEs通过上调Sp1表达促进结直肠癌的迁移和侵袭
DOI：
10.1016/j.bbagen.2017.02.024
复制
发表时间：
2017-05-01
影响因子：
3
通讯作者：
Su, Qing
中科院分区：
文献类型：
--
作者：
Deng, Ruyuan;Wu, Huo;Su, Qing
糖尿病患者发生结直肠癌（CRC）的风险明显增加。作为体内积累的晚期糖基化终产物（AGEs）的主要形式之一，葡萄糖源性AGEs在糖尿病并发症的发病机制中起着重要作用，并可能促进结直肠癌的进展。然而，迄今为止，葡萄糖来源的AGEs对结直肠癌病程的贡献及其潜在机制尚不清楚。在本研究中，结直肠癌患者血清和肿瘤组织中葡萄糖源性AGEs浓度升高。临床资料分析表明，中国汉族结直肠癌患者癌组织中AGEs受体（RAGE）、特异性蛋白1 （Sp1）和基质金属肽酶-2 （MMP2）的表达明显高于非肿瘤组织，且RAGE表达与淋巴结转移和TNM分期密切相关。此外，体内和体外实验表明，AGEs促进结直肠癌的侵袭和迁移，AGEs处理使RAGE、Sp1和MMP2的表达呈剂量依赖关系。RAGE阻断抗体和sp1特异性siRNA减弱了age诱导的作用。此外，AGEs处理增加了ERK的磷酸化水平，MEK1/2抑制剂降低了ERK的磷酸化水平，降低了Sp1的表达。综上所述，葡萄糖来源的AGEs通过RAGE/ERK/SP1/MMP2级联促进结直肠癌的侵袭和转移。这些发现可能解释了糖尿病患者结直肠癌预后不良的原因。(C) 2017 Elsevier B.V.版权所有
It is well established that the risk of colorectal cancer (CRC) is significantly increased in diabetic patients. As one of main forms of the advanced glycation end products (AGEs) that accumulate in vivo, glucose-derived AGEs play an important role in the pathogenesis of diabetic complications and may contribute to CRC progression. However, to date, both the contribution of glucose-derived AGEs to the course of CRC and the underlying mechanism are unclear. In the present study, the concentration of glucose-derived AGEs in the serum and tumor tissue of patients with CRC increased. A clinical data analysis demonstrated that the expression of the receptor for AGEs (RAGE), Specificity Protein 1 (Sp1), and matrix metallopeptidase -2 (MMP2) was significantly higher in cancerous tissues compared with non-tumor tissue in Chinese Han patients with CRC and that RAGE expression was closely associated with lymph node metastasis and TNM stage. Furthermore, in vivo and in vitro experiments showed that AGEs promoted invasion and migration of colorectal cancer, and the AGEs treatment increased the expression of RAGE, Sp1, and MMP2 in a dose-dependent manner. A RAGE blocking antibody and an Sp1-specific siRNA attenuated the AGE-induced effects. Moreover, the AGEs treatment increased the phosphorylation of ERK, and reducing the phosphorylation level of ERK by MEK1/2 inhibitor decreased the expression of Sp1. In conclusion, glucose-derived AGEs promote the invasion and metastasis of CRC partially through the RAGE/ERK/SP1/MMP2 cascade. These findings may provide an explanation for the poor prognoses of colorectal cancer in diabetic patients. (C) 2017 Elsevier B.V. All rights reserved.