Hypoxia Inducible Transcription Factor (Hif-1) Regulates Cxcl13 Expression: Clinical Implications In Pediatric Non-Hodgkin'S Lymphoma

Background: Lymphomas are B and/or T cell clonal neoplasms in various states of differentiation, characteristically compromising lymph nodes. They are constituted by B and T lymphocytes that reach the node by chemokine-mediated recruitment including CXCL13. Hypoxia-inducible transcription factor ( HIF-1 alpha) plays a role in cellular adaptation to oxygen concentration changes. It also regulates expression of chemokines such as CXCL12, CCL20, and CCL5 as well as some of their receptors such as CCR7 and CXCR4.Methods: We performed in silico analysis of the CXCL13 promoter, pharmacologic modulation of HIF-1 alpha activity and, using reporter plasmids, site-directed mutation and DNA-protein interaction analysis we analyzed the relation between HIF-1 alpha activity and CXCL13 expression. Moreover, we did tissue microarray and immunohistochemistry to see the expression of HIF-1 alpha and CXCL13.Results: This study detected three possible HIF-1 alpha binding sites suggesting that this chemokine may be regulated by the CXCL13 transcription factor. We showed that CXCL13 expression is directly dependent, whereby an increase in HIF-1 alpha activity increases CXCL13 expression and decreased HIF-1 alpha activity in turn decreases CXCL13 expression. We proved that HIF-1 alpha transcriptionally regulates the expression of CXCL13 in a direct manner. We established that HIF-1 alpha and CXCL13 are greatly overexpressed in the most aggressive pediatric lymphomas.Conclusions: For the first time, this study showed that HIF-1 alpha directly regulates transcriptional CXCL13 and that both proteins are overexpressed in the most aggressive forms of pediatric lymphoma. This suggests that they may play a significant role in the pathogenesis of pediatric non-Hodgkin's lymphoma. (c) 2013 Boletin Medico del Hospital Infantil de Mexico. Published by Masson Doyma Mexico S.A. All rights reserved.