基于PPARγ对糖转运及代谢的影响探讨罗格列酮对糖尿病小鼠胰腺癌模型的作用机制  

Mechanism of effect of rosiglitazone on pancreatic cancer in diabetic mice based on impact of PPARγon glucose transport and metabolism

作　　者：胡瑞萍 尚利峰 王和静 车红霞 王明亮 杨欢 靳媛媛 张菲菲 张建岭 HU Rui-ping;SHANG Li-feng;WANG He-jing;CHE Hong-xia;WANG Ming-liang;YANG Huan;JIN Yuan-yuan;ZHANG Fei-fei;ZHANG Jian-ling(Third People′s Hospital of Gansu Province,Lanzhou 730000,China;Qingdao Eighth People′s Hospital,Qingdao Shandong 266121;The First Hospital of Lanzhou University,Lanzhou 730000,China)

机构地区：[1]甘肃省第三人民医院,甘肃兰州730000 [2]青岛市第八人民医院,山东青岛266121 [3]兰州大学第一医院,甘肃兰州730000

出　　处：《中国药理学通报》2024年第7期1325-1334,共10页Chinese Pharmacological Bulletin

基　　金：甘肃省科技厅自然科学基金资助项目(No 21JR7RA670)。

摘　　要：目的基于PPARγ对糖转运及代谢的影响探讨罗格列酮(rosiglitazone,Rsg)对糖尿病小鼠胰腺癌模型的作用机制。方法采用高脂高糖饮食+STZ建造T2DM模型;选择造模成功的T2DM小鼠和正常小鼠,建造PANC02细胞移植瘤模型。T2DM移植瘤小鼠和正常移植瘤小鼠分组均为:Rsg;PPARγ抑制剂(PIN-2);Rsg+PPARγ抑制剂(Rsg+PIN-2),并分别以正常移植瘤小鼠(NDM)和T2DM移植瘤小鼠(DM)作为对照组。干预后取材;HE染色观察组织病理变化;免疫组化检测组织中Ki67和PCNA的表达;TUNEL检测细胞凋亡情况;免疫荧光检测PPARγ的表达;RT-PCR法测定Glucokinase、GLUT2、Nkx6.1、PDX-1 mRNA的表达;Western blot检测Glucokinase、GLUT2、Nkx6.1、PDX-1蛋白的表达。结果Rsg可使NDM和DM小鼠移植瘤质量、病理变化、Ki67和PCNA的表达均明显降低(P<0.05),细胞凋亡和PPARγ、Glucokinase、GLUT2、Nkx6.1、PDX-1表达均明显升高(P<0.05);PIN-2均可逆转Rsg导致的NDM和DM小鼠指标变化;与NDM小鼠比,DM组小鼠上述相关指标对Rsg和PIN-2更加敏感。结论相比于非糖尿病胰腺癌,Rsg可更加敏感地通过激活PPARγ抑制糖尿病胰腺癌的增殖,诱导其凋亡,并通过改变糖脂代谢基因,重编程胰腺癌代谢,进而达到抑癌的作用。Aim To explore the mechanism of the effect of rosiglitazone(Rsg)on the pancreatic cancer in diabetic mice based on the impact of PPARγon glucose transport and metabolism.Methods A high-fat and high sugar diet combined with STZ was used to construct T2DM model;T2DM mice and normal mice were subcutaneously injected with PANC02 cells to construct a transplanted tumor model.T2DM transplanted tumor mice and normal transplanted tumor mice were divided into the following groups:Rsg,PPARγinhibitor(PIN-2),rosiglitazone+PPARγinhibitor(Rsg+PIN-2),and normal transplanted tumor mice(NDM)and T2DM transplanted tumor mice(DM)were used as control groups,respectively.Tissue samples were collected after intervention.Tissue pathological changes were observed by HE staining.The expressions of Ki67 and PCNA proteins were detected by immunohistochemistry.Cell apoptosis was detected by TUNEL assay.The expression of PPARγwas detected by immunofluorescence.The expressions of Glucokinase,GLUT2,Nkx6.1,PDX-1RT-PCR were determined by Western blot.Results Rsg could significantly reduce the tumor mass,pathological changes,Ki67 and PCNA expression of transplanted tumors(P<0.05),increase cell apoptosis and the expression of PPARγ,Glucokinase,GLUT2,Nkx6.1,PDX-1 proteins in NDM and DM mice(P<0.05).PIN-2 could reverse the indicator changes caused by Rsg in NDM and DM mice.However,compared with NDM mice,the above related indicators of the DM group mice were more sensitive to Rsg and PIN-2.Conclusions Compared to non-diabetic pancreatic cancer,rosiglitazone can more sensitively inhibit the proliferation of pancreatic cancer with T2DM,induce apoptosis,and reprogram the metabolism of pancreatic cancer with T2DM by activating PPARγand altering the expression of glucose and lipid metabolism genes,thereby exerting an anti-cancer effect.

关 键 词：罗格列酮 PPARΓ 2型糖尿病 胰腺癌 糖转运 抑癌 

分 类 号：R-332[医药卫生] R343R587.1R735.9R977.15