糖尿病异常O-GlcNAc糖基化修饰与恶性肿瘤的发生密切相关。申请者前期研究证实：miR-191在肝内胆管细胞癌中高表达，且通过降低DNA甲基化羟化酶TET1的表达促进肿瘤的恶性进展；近期实验发现：高糖能上调miR-191表达，且高糖和O-GIcNAc转移酶均能促进ICC增殖并抑制其凋亡；过表达miR-191可促进氨基己糖合成途径（HBP）相关的糖代谢产物的生成和糖消耗的增加，促进O-GlcNAc糖基化。因此，申请者认识到：高糖通过上调miR-191，抑制其靶基因TET1表达，进而促进O-GlcNAc糖基化，导致ICC的进展。本项目拟研究：①在细胞和动物水平探索糖尿病促进ICC发展的分子机制；②ICC伴糖尿病患者和ICC患者O-GlcNAc、miR-191、TET1的差异性表达；③ICC伴糖尿病患者O-GlcNAc糖基化水平与miR-191、TET1表达的相关性。

Abnormal O-GlcNAcylation glycosylation of diabetes mellitus is closely related to the progression of malignancies.Our previous study found that miR-191 was highly expressed in the intrahepatic cholangiocarcinoma(ICC), and it could promote its malignant progression by reducing the expression of DNA methylated hydroxylase TET1. Our recent findings indicated that high glucose increased the expression of miR-191. Besides, high glucose and O-GIcNAc transferase could promote the proliferation of ICC cells and inhibit their apoptosis. In addition, overexpression of miR-191 facilitated the generation of glucose metabolites associated with hexosamine biosynthetic pathway(HBP) and increased the sugar consumption, promoting O-GlcNAcylation glycosylation. Based on the above findings, the applicant recognizes that high glucose increases miR-191 expression, resulting in the inhibition of TET1 expression and the enhancement of O-GlcNAcylation glycosylation, thereby contributing to the development of ICC.This project intends to study: ①the molecular mechanism of diabetes mellitus promoting ICC development in vivo and in vitro (increased expression of microRNA-191, O-GlcNAc glycosylation modification); ②the differential expression of O-GlcNAc, microRNA-191 and TET1 in ICC patients with diabetes mellitus and ICC patients; ③the correlation between the glycosylation level of O-GlcNAc and the expression of microRNA-191 and TET1 in ICC patients with diabetes mellitus.