RETRACTED ARTICLE: CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma
- 1.1k Downloads
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.
KeywordsCXCR4 EMT PI3K/AKT ERK Glioblastoma
This study was supported by Science and Technology Project of Shandong Province Academy of Medical Sciences (2013015). We greatly thank other members of the Yang and Sandy Lab for their valuable suggestions and writing.
Conflicts of interest
The authors state that there are no conflicts of interest to disclose.
- 3.Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn Martin JB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996CrossRefPubMedGoogle Scholar
- 4.Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ, Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31(32):4085–4091CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117(12):3810–3820PubMedPubMedCentralGoogle Scholar