title: CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma.
abstract: Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in tumor progression. Epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. This study aimed to investigate the roles and underlying mechanisms of SDF-1/CXCR4 axis in EMT process of glioblastoma. In the present study, CXCR4 activation and inhibition in U87 were induced with exogenous SDF-1 and with CXCR4 small interfering RNA (siRNA), respectively. CXCR4 downstream signal molecules AKT, ERK, and EMT biomarkers (vementin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. Our results showed that SDF-1 can induce AKT and ERK phosphorylation in a dose-dependent manner, and endogenous CXCR4 can be blocked thoroughly by CXCR4 siRNA in U87. Notably SDF-1 alone treatment can induce the upregulation of vementin, snail, and N-cadherin of U87; besides, the downregulation of E-cadherin also occurred. On the contrary, CXCR4 siRNA significantly prohibited SDF-1-induced AKT and ERK phosphorylation, at the same time, EMT biomarker changes were not observed. Function analysis revealed that CXCR4 siRNA obviously interfered with U87 cell migration and proliferation, according to wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then involved in the tumor cell invasion and proliferation via activation of PI3K/AKT and ERK pathway. Our study lays a new foundation for the treatment of glioblastoma through antagonizing CXCR4.
authors.affiliation: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors.forename: Baoyu
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Pathology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China.
authors.forename: Xiangshan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pathology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China.|Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Shunzeng
authors.initials: S
authors.lastname: Lv
authors.affiliation: Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China.
authors.forename: Kaixi
authors.initials: K
authors.lastname: Fan
authors.affiliation: Shandong University School of Medicine, Jinan, Shandong, China.|Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors.forename: Fengling
authors.initials: F
authors.lastname: Wang
authors.affiliation: Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Huishu
authors.initials: H
authors.lastname: Song
authors.affiliation: Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors.forename: Xuefen
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pathology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China.
authors.forename: Man
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, No, 440 Jiyan Road, Jinan, 250117, Shandong, China. sdzhanglisd@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014746:Vimentin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D015820:Cadherins; D054377:Chemokine CXCL12; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: CXCR4; EMT; ERK; Glioblastoma; PI3K/AKT