Migfilin promotes migration and invasion in glioma by driving EGFR and MMP-2 signalings:A positive feedback loop regulation  

作　　者：Yunwei Ou Qingnan Wu Chuanyue Wu Xuefeng Liu Yongmei Song Qimin Zhan 

机构地区：[1]Department of Neurosurgery,Beijing Tiantan Hospital,Capital Medical University,Beijing 100050,China [2]Beijing Neurosurgical Institute,Capital Medical University,Beijing 100050,China [3]State Key Laboratory of Molecular Oncology,National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [4]Department of Pathology,University of Pittsburgh,Pittsburgh 15261,USA [5]Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment,South University of Science and Technology of China,Shenzhen 518055,China [6]china National Clinical Research Center for Neurological Diseases,BeUing 100050,China

出　　处：《Journal of Genetics and Genomics》2017年第12期557-565,共9页遗传学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81502150,81472661,81490753,81230047 and 81672743);the National Basic Research Program of China(Nos.2012CB967003 and 2015CB553904);the National key research and development program of China(No.2016YFA0500303);the CAMS Innovation Fund for Medical Sciences(2016-I2M-1-001);the Young Foundation of Beijing Tiantan Hospital of Capital Medical University(2014-YQN-YS-02);the Beijing Outstanding Talent Training Project(2015000021469G222);the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2014BAI04B01,2015BAI12B04 and 2013BAI09B03);supported by NIH grants(AR064874 and AR068950)

摘　　要：Glioma is the most common type of primary brain tumors in the central nervous system（CNS）. Migfilin occurs in human glioma and enhances cellular motility via the epidermal growth factor receptor（EGFR）pathway. However, the underlying molecular mechanism is not fully understood. In this study, we found that Migfilin promoted matrix metalloproteinase-2（MMP-2） activity, and restrained the expression of tissue inhibitor of metalloproteinase 2（TIMP2）, which is an MMP-2 inhibitor. Functional and structural studies showed that the LIM1 domain of Migfilin was required for Migfilin-mediated TIMP2 expression inhibition and MMP-2 activity, and was also necessary in promoting cell motility. Furthermore, Migfilininduced EGFR phosphorylation was greatly reduced by MMP-2 inhibitor（GM6001） or si RNA, while Migfilin-induced MMP-2 activation was also blocked by the EGFR inhibitor（AG1478） or si RNA. MMP-2 and EGFR inhibitors and their si RNAs can block Migfilin-induced migration and invasion, respectively.These results demonstrated that EGFR and MMP-2 signalings may form a positive feedback loop to enhance Migfilin-induced migration and invasion. Finally, we detected that the expression of Migfilin,EGFR phosphorylation（Tyr1173） and MMP-2 activity had a positive correlation in the clinical glioma sample. Taken together, these results suggest that Migfilin is a critical regulator in cellular motility by driving the EGFR-MMP-2 feedback loop, and may be considered as a potential therapeutic target in glioma.Glioma is the most common type of primary brain tumors in the central nervous system（CNS）. Migfilin occurs in human glioma and enhances cellular motility via the epidermal growth factor receptor（EGFR）pathway. However, the underlying molecular mechanism is not fully understood. In this study, we found that Migfilin promoted matrix metalloproteinase-2（MMP-2） activity, and restrained the expression of tissue inhibitor of metalloproteinase 2（TIMP2）, which is an MMP-2 inhibitor. Functional and structural studies showed that the LIM1 domain of Migfilin was required for Migfilin-mediated TIMP2 expression inhibition and MMP-2 activity, and was also necessary in promoting cell motility. Furthermore, Migfilininduced EGFR phosphorylation was greatly reduced by MMP-2 inhibitor（GM6001） or si RNA, while Migfilin-induced MMP-2 activation was also blocked by the EGFR inhibitor（AG1478） or si RNA. MMP-2 and EGFR inhibitors and their si RNAs can block Migfilin-induced migration and invasion, respectively.These results demonstrated that EGFR and MMP-2 signalings may form a positive feedback loop to enhance Migfilin-induced migration and invasion. Finally, we detected that the expression of Migfilin,EGFR phosphorylation（Tyr1173） and MMP-2 activity had a positive correlation in the clinical glioma sample. Taken together, these results suggest that Migfilin is a critical regulator in cellular motility by driving the EGFR-MMP-2 feedback loop, and may be considered as a potential therapeutic target in glioma.

关 键 词：GLIOMA Migfilin MMP-2 EGFR MOTILITY 

分 类 号：R739.41[医药卫生—肿瘤]