title: Glucose-derived AGEs promote migration and invasion of colorectal cancer by up-regulating Sp1 expression.
abstract: 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.
authors.affiliation: Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665, Kong Jiang Road, Shanghai 200092, China.
authors.forename: Ruyuan
authors.initials: R
authors.lastname: Deng
authors.affiliation: Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Huo
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665, Kong Jiang Road, Shanghai 200092, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ran
authors.affiliation: Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665, Kong Jiang Road, Shanghai 200092, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Kong
authors.affiliation: Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Hu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address: wangxiao1976@hotmail.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665, Kong Jiang Road, Shanghai 200092, China. Electronic address: suqingxinhua@163.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
mesh_terms: D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D017127:Glycation End Products, Advanced; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D020778:Matrix Metalloproteinase 2; D005947:Glucose
keywords: AGEs; Colorectal cancer; Invasion; Migration; RAGE; Sp1