HIF‐1α mediates CXCR4 transcription to activate the AKT/mTOR signaling pathway and augment the viability and migration of activated B cell‐like diffuse large B‐cell lymphoma cells

Abstract

AbstractDiffuse large B‐cell lymphoma (DLBCL) is the most common lymphoid malignancy with a high relapse rate. We previously found that C‐X‐C motif chemokine receptor 4 (CXCR4) was highly expressed in DLBCL and associated with poor prognosis. This study focused on the effect of hypoxia‐inducible factor‐1α (HIF‐1α) on CXCR4 expression and the DLBCL progression. Two activated B cell‐like DLBCL cell lines Ly‐3 and SUDHL2 were transfected with overexpression and knockdown plasmids or HIF‐1α. The viability and migration of DLBCL cells were significantly increased under hypoxic conditions, or upon HIF‐1α overexpression under normoxic conditions, but the HIF‐1α downregulation led to inverse trends. However, the promoting effects of HIF‐1α overexpression on DLBCL cells were suppressed by Plerixafor (a CXCR4 inhibitor). The luciferase and chromatin immunoprecipitation assays revealed that HIF‐1α bound to the functional site HRE1 on CXCR4 promoter to activate its transcription. HIF‐1α‐mediated CXCR4 activation further led to increased phosphorylation of AKT/mTOR under hypoxic conditions. Taken together, this work reports that HIF‐1α promotes viability and migration of activated B cell‐like cells under hypoxia, which might involve the transcription of CXCR4 and the activation of the AKT/mTOR pathway. The finding may provide novel lights in the management of DCBCL.