Kaposi's sarcoma (KS) is the most common cancer among HIV-positive patients. Histogenetic origin of KS has long been elusive due to a mixed expression of both blood and lymphatic endothelial markers in KS tumor cells. However, we and others discovered that Kaposi's sarcoma herpes virus (KSHV) induces lymphatic reprogramming of blood vascular endothelial cells by upregulating PROX1, which functions as the master regulator for lymphatic endothelial differentiation. Here, we demonstrate that the KSHV latent gene kaposin-B enhances the PROX1 mRNA stability and plays an important role in KSHV-mediated PROX1 upregulation. We found that PROX1 mRNA contains a canonical AU-rich element (ARE) in its 3′-untranslated region that promotes PROX1 mRNA turnover and that kaposin-B stimulates cytoplasmic accumulation of the ARE-binding protein HuR through activation of the p38/MK2 pathway. Moreover, HuR binds to and stabilizes PROX1 mRNA through its ARE and is necessary for KSHV-mediated PROX1 mRNA stabilization. Together, our study demonstrates that kaposin-B plays a key role in PROX1 upregulation during lymphatic reprogramming of blood vascular endothelial cells by KSHV.
Kaposi's sarcoma (KS) is the most common cancer in HIV-positive patients and KS-associated herpes virus (KSHV) was identified as its causing agent. We and others have discovered that when the virus infects endothelial cells of blood vessels, KSHV reprograms the cell type resembling endothelial cells in lymphatic vessels. Although endothelial cells of the blood vascular system and of the lymphatic system share functional similarities, the cell type-reprogramming does not occur under a normal physiological condition. Therefore, cell-fate reprogramming by the cancer-causing virus KSHV provides an important insight into the molecular mechanism for viral pathogenesis. Our current study investigates the molecular mechanism underlying the KSHV-mediated cell fate reprogramming. We identified that a KSHV latent gene kaposin-B plays an important role in KSHV-mediated regulation of PROX1 to promote PROX1 mRNA stability. This study will provide a better understanding on the tumorigenesis and pathogenesis of KS with a potential implication toward new KS therapy.
|ScienceOpen disciplines:||Infectious disease & Microbiology|