内源性HMGB1调节低氧乏养胰腺癌细胞脂肪酸代谢及其机制  

Endogenous HMGB1 Modulates Fatty Acid Metabolism of Hypoxic and Nutrient-poor Pancreatic Cancer Cells and Related Mechanism

作　　者：高洁 吴琪炜 宋廉[1] 石卉[1] 王鸣[1] 龚爱华[2] 王冬青[1] 朱海涛[1] GAO Jie;WU Qiwei;SONG Lian;SHI Hui;WANG Ming;GONG Aihua;WANG Dongqing;ZHU Haitao(Department of Radiology,Affiliated Hospital of Jiangsu University,Zhenjiang 212001,China;School of Medicine,Jiangsu University,Zhenjiang 212013,China)

机构地区：[1]江苏大学附属医院影像科,镇江212001 [2]江苏大学医学院,镇江212013

出　　处：《肿瘤防治研究》2021年第7期667-673,共7页Cancer Research on Prevention and Treatment

基　　金：江苏省自然基金(BK20191223);江苏省卫生厅重点项目(K2019024);江苏省六个一项目(LGY2018093);中华国际医学交流基金会SKY影像科研项目(Z-2014-07-1912-18);镇江市社会发展项目(SH2020031)。

摘　　要：目的研究内源性高迁移率族蛋白B1(HMGB1)在低氧乏养胰腺癌细胞脂肪酸代谢重编程及线粒体融合/分裂中的作用及机制。方法GEPIA数据库分析胰腺癌组织中HMGB1表达水平与胰腺癌患者生存率的相关性;CCK-8法、划痕实验和Transwell实验分别检测内源性HMGB1对低氧乏养Patu8988细胞增殖、侵袭及迁移的作用;激光共聚焦显微镜观察Patu8988细胞线粒体形态的改变;蛋白质免疫印迹法检测细胞线粒体融合/分裂相关蛋白、脂肪酸从头合成相关蛋白表达水平的影响。结果GEPIA数据库分析结果表明HMGB1在胰腺癌中高表达(P<0.01),且表达水平与胰腺癌患者生存时间呈负相关(P=0.00097);干扰低氧乏养Patu8988细胞的HMGB1后,细胞增殖、侵袭及迁移能力降低,Patu8988细胞线粒体形态分裂增加,线粒体分裂相关蛋白FIS1表达增加,p-DRP1(Ser637)表达降低,融合相关蛋白MFN1和MFN2表达降低;ACLY、p-ACLY和FASN蛋白表达水平均下降。结论内源性HMGB1可以促进低氧乏养胰腺癌Patu8988细胞线粒体的融合,抑制分裂,维持线粒体的形态和功能,从而上调ACLY蛋白的表达及磷酸化水平,促进Patu8988细胞的脂肪酸(FA)合成,维持胰腺癌细胞增殖、侵袭及迁移能力。Objective To explore the role and mechanism of HMGB1 in the fatty acid metabolism reprogramming and mitochondrial fusion/fission of hypoxic and nutrient-poor pancreatic cancer cells.Methods The correlation between the expression level of HMGB1 in pancreatic cancer tissue and the survival rate of pancreatic cancer patients were analyzed by GEPIA database.CCK-8 assay was used to measure cell proliferation rate,and scratch test and Transwell chamber method were carried out to detect the effects of endogenous HMGB1 on the invasion and migration abilities of human pancreatic cancer cell line Patu8988 after hypoxic and nutrient-poor treatment.Laser confocal microscope was used to observe the changes of mitochondrial morphology of Patu8988 cells.Western blot was used to detect the expression levels of mitochondrial fusion/fission and de novo fatty acid synthesis-related proteins.Results GEPIA database analysis results showed that HMGB1 was highly expressed in pancreatic cancer tissues(P<0.01),and the expression level was negatively correlated with the survival time of pancreatic cancer patients(P=0.00097).Knockdown of HMGB1 expression could inhibit the proliferation,invasion and migration abilities of Patu8988 cells under hypoxic and nutrient-poor conditions.However,mitochondrial fission in patu8988 cells was increased.Knockdown of HMGB1 in Patu8988 cells increased the expression of fission-related protein FIS1 while decreased the expression of p-DRP1(Ser637)and fusion-related protein MFN1 and MFN2 in hypoxic and nutrient-poor environment;ACLY,p-ACLY and FASN protein expression levels were down-regulated.Conclusion Endogenous HMGB1 can promote the fusion and inhibit the fission of mitochondria in hypoxic and nutrient-poor Patu8988 cells,maintain mitochondrial morphology and function,and thereby up-regulate ACLY protein expression and phosphorylation level,promote FA synthesis,and maintain the proliferation,invasion and migration abilities of pancreatic cancer cells.

关 键 词：低氧乏养 高迁移率族蛋白B1 脂肪酸从头合成 线粒体分裂/融合 胰腺癌 

分 类 号：R735.9[医药卫生—肿瘤]