B-Raf-dependent expression of vascular endothelial growth factor-A in Kaposi sarcoma-associated herpesvirus-infected human B cells.

Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) is etiologically linked to Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease. Vascular endothelial growth factor-A (VEGF-A) is one of the essential factors required in KSHV pathogenesis, mainly due to its ability to mediate angiogenesis. In this report we analyzed the relationship between Raf and VEGF-A expression in KSHV-infected hematopoietic cells. All of the KSHV-infected cell lines (derived from PEL) expressed higher levels of B-Raf and VEGF-A when compared with uninfected cells. Inhibition of Raf to mitogen-induced extracellular kinase (MEK) to extracellular signal-related kinase (ERK) signaling, either by the use of MEK inhibitor (PD98059) or by siRNA specific to B-Raf, significantly lowered VEGF-A expression. In addition, B-Raf-induced VEGF-A expression was demonstrated to be sufficient to enhance tubule formation in endothelial cells. Interestingly, we did not observe mutation in the B-Raf gene of the KSHV-infected PEL cell lines. Taken together, we report for the first time the ability of Raf-associated signaling to play a role in the expression of VEGF-A in KSHV-infected hematopoietic cells.