Role of Macrophage Migration Inhibitory Factor (MIF) in KSHV-associated Malignancies

Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients (e.g., HIV+ personnel or organ transplant recipients) and lack of effective therapeutic options. Despite the reduced incidence of KS in the era of combined Antiretroviral Therapy (cART) for HIV infection, KS especially oral KS still remains one of the most common AIDS-associated tumors and a leading cause of morbidity and mortality in this setting. PEL is a rapidly progressing malignancy with a median survival time of approximately 6 months, even under the combinational chemotherapy. Macrophage migration inhibitory factor (MIF) signaling activation have been found closely related to many cancer cell malignant behaviors, however, its role in virus-associated cancers or how oncogenic viruses may regulate MIF signaling activities remain largely unknown. We recently found high levels of MIF signaling activities during KSHV infection or KSHV+ tumor cells in vitro and in vivo. Thus, we hypothesize that MIF signaling activation has important role in KSHV pathogenesis and oncogenesis, which may represent a promising direction to develop anticancer treatments for KSHV-related malignancies. To address this hypothesis, we propose the following Specific Aims: 1) To determine the underlying mechanisms of MIF signaling activation within KSHV+ tumor cells. 2) To develop MIF-targeted therapies against KSHV-related malignancies. Through these efforts, we hope to determine the roles of MIF signaling activation in KHSV pathogenesis and induced oncogenesis, and develop MIF signaling targeted therapies for improving the outcome of KSHV-related malignancies in high-risk immunocompromised patients.