LincRNA-p21抑制Muc1对糖尿病促进胰腺癌发生及转移的阻止作用与机制研究

Diabetes and pancreas cancer are diseases which take the size of an epidemic spread across the globe. Those diseases are influenced by many factors, both genetic and environmental. Precise knowledge of the complex relationships and interactions between these two conditions is of great importance for their prevention and treatment. Many epidemiological studies have shown that pancreas cancer is more common in patients with diabetes or related metabolic disorders. Epidemiological studies, however, do not say anything about the mechanisms of these dependencies. For this purpose, molecular research is needed on the metabolism of cells (including tumor cells) and on metabolic dysfunctions that arise due to changes in the cell environment taking place in the sick, as well as in the intensely treated human organism. Increasing evidence suggests that large intervening non-coding RNAs (lincRNAs) regulate key pathways in cancer invasion and metastasis. LincRNA-p21 serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. Our perlimited data suggested that Muc1 enhances hyperglycemia-induced pancreas cancer cells EMT (epithelial mesenchymal transition) and cells migration, however, LincRNA-p21 inhibits the process above mentioned. Also LincRNA-p21 induces pancreas cancer cells undergoing apoptosis even the cancer cells in high glucose environment. The aims of this project are to determine the biological function of Muc1 on Diabetes-facilitated pancreas carcinogenesis and tumor early metastasis, and to confirm that LincRNA-p21 inhibits Muc1 results in blockage pancreas carcinogenesis and tumor metastasis. In this project, we will focus on the key point of LincRNA-p21, use functional deficiency or achieve experiments, gene CHIP technique in enormous of clinic samples, transgenic mouse model and in vitro. We expectedly would find out the connected point of diabetes and pancreas cancer, and supply a new target for early diagnosis and biological therapy.

胰腺癌发病隐匿，早期确诊率低，死亡率极高。目前认为糖尿病是胰腺癌早期表现及致病因素，两病均属慢性炎症性疾病，但是两者的关联及胰腺癌发病机制均未阐明。长链非编码RNA（LincRNA）与多种肿瘤发生和转移密切相关，我们的预实验表明Muc1对高糖引起的胰腺癌细胞上皮间质转化(EMT)和细胞迁移都有促进作用，LincRNA-p21不仅能抑制EMT形成，而且还可诱导胰腺癌细胞凋亡，即使在高糖环境中，这一作用仍然存在。本研究拟利用临床标本、转基因动物模型和体外培养胰腺癌细胞，以LincRNA-p21对Muc1作用为切入点，利用功能获得与缺失实验、基因芯片技术和细胞分子生物学技术开展研究，以确定：⑴Muc1在糖尿病促进胰腺癌发生并早期转移中的作用；⑵LincRNA-p21抑制Muc1进而阻止胰腺癌发生和转移的作用。以期找出两病关联的结合点，并以此为靶点建立胰腺癌早期诊断体系和新的生物治疗方法。

胰腺癌发病隐匿，早期确诊率低，死亡率极高。目前认为糖尿病是胰腺癌早期表现及致病因素，两病均属慢性炎症性疾病，但目前对两者之间的相互影响及连接点了解甚少。长链非编码RNA（LincRNA）与多种肿瘤发生和转移密切相关，我们的前期研究也提示此现象的存在，但确切关联及机制不清。故本项目在预实验基础上从临床标本、动物实验和细胞实验开展了相关研究，以LincRNA-p21对Muc1作用为切入点，利用功能获得与缺失实验、基因芯片技术和细胞分子生物学技术开展研究。主要研究内容为确定Muc1在糖尿病促进胰腺癌发生并早期转移中的作用及LincRNA-p21抑制Muc1进而阻止胰腺癌发生和转移的作用。本研究证实血CA19-9和CEA水平，是发现糖尿病患者罹患胰腺癌的敏感指标；2型糖尿病患者蛋白代谢紊乱和促胰岛素分泌剂的使用，可能会引起血清CA19-9值的轻度升高。Muc1在胰腺癌和糖尿病中均有异常的高表达，是糖尿病与胰腺癌互为影响的关键连接因子；LincRNA-p21对胰腺癌的发生和转移有抑制作用，其作用靶点是Muc1。高糖可抑制胰腺癌细胞的自噬，而二甲双胍能诱导胰腺癌细胞自噬，并阻止高糖对胰腺癌细胞自噬的抑制。研究结果为阐明胰腺癌，尤其是糖尿病患者胰腺癌发生机制、为临床常用降糖药物--二甲双胍在抑制胰腺癌发生发展中的作用及机制阐明提供了理论依据；也为糖尿病人群，即胰腺癌的高危人群，早期预测及有效防治提供了新思路新方法，具有深远的社会效益和经济效益；研究还为糖尿病与不同肿瘤形成间的关系及机制研究提供了新思路和实验依据。