Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. Kaposi's sarcoma-associated herpesvirus (KSHV) replication and ongoing infection of target cells plays an important role in KS pathogenesis. An amino acid membrane transport protein subunit, xCT, maintains intracellular glutathione stores to enhance the survival of cells producing reactive nitrogen species (RNS), and xCT was recently identified as a fusion-entry receptor for KSHV (Kaleeba and Berger, Science, 2006). A number of intracellular and extracellular triggers regulate xCT expression, including binding of the xCT promoter by transcription regulators and the activation of positive transcription regulators by RNS. We have determined recently that xCT is expressed by multiple cell types within KS lesions and circulating mononuclear cells from HIV-infected patients, with cells from KSHV/HIV co-infected patients exhibiting the highest xCT expression. However, it is unknown whether KSHV itself regulates xCT expression to promote KSHV infection and persistence in the local environment. KSHV infects macrophages within KS lesions, and macrophages are a principal source of RNS. Using a novel macrophage cell culture system, our preliminary data suggest that KSHV microRNA suppress BACH-1, a negative transcription regulator of xCT expression, and that KSHV induces RNS secretion by macrophages. Based on these preliminary data, we hypothesize that KSHV promotes its own persistence in the local environment by upregulating xCT expression through both paracrine and autocrine mechanisms, and that targeting xCT regulatory pathways reduces KSHV infection and persistence in the microenvironment. To address this hypothesis, we propose two independent aims: 1) to determine mechanisms and functional outcomes for xCT regulation by KSHV;and 2) to determine clinical relationships between KSHV infection, xCT expression and RNS production in HIV-infected patients at greatest risk for KS. Through these efforts, we hope to provide the framework for developing novel therapeutic strategies for KS through the targeting of xCT and the reduction of KSHV infection and persistence within the tumor microenvironment.
Tumors etiologically linked to the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), including Kaposi's sarcoma (KS), are among the most common tumors encountered in the setting of HIV infection and other forms of immune suppression. KS remains an important cause of morbidity and mortality for these patients in the modern era, and the efficacy and toxicity of available therapies for KS are limiting. Therefore, understanding mechanisms for how KSHV regulates expression of its own receptors and the longevity of KSHV-infected cells could provide a scientific basis for developing novel preventive and therapeutic targets for KS.
|Kadri, Ferdous; LaPlante, Andrea; De Luca, Mariacristina et al. (2016) Defining Plasma MicroRNAs Associated With Cognitive Impairment In HIV-Infected Patients. J Cell Physiol 231:829-36|
|Dai, Lu; Qiao, Jing; Nguyen, David et al. (2016) Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus. Oncotarget 7:10459-71|
|Dai, Lu; Trillo-Tinoco, Jimena; Chen, Yihan et al. (2016) CD147 and downstream ADAMTSs promote the tumorigenicity of Kaposi's sarcoma-associated herpesvirus infected endothelial cells. Oncotarget 7:3806-18|
|Katz, Paige S; Siggins, Robert W; Porretta, Connie et al. (2015) Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques. Alcohol 49:759-65|
|Dai, Lu; Trillo-Tinoco, Jimena; Cao, Yueyu et al. (2015) Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood 126:2821-31|
|Dai, Lu; Chen, Yihan; Bonstaff, Karlie et al. (2015) Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients. Cancer Lett 362:158-66|
|Qin, Zhiqiang; Dai, Lu; Trillo-Tinoco, Jimena et al. (2014) Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol Cancer Ther 13:154-64|
|Dai, Lu; Cao, Yueyu; Chen, Yihan et al. (2014) Targeting xCT, a cystine-glutamate transporter induces apoptosis and tumor regression for KSHV/HIV-associated lymphoma. J Hematol Oncol 7:30|
|Dai, Lu; Bai, Lihua; Lu, Ying et al. (2013) Emmprin and KSHV: new partners in viral cancer pathogenesis. Cancer Lett 337:161-6|
|Qin, Zhiqiang; Dai, Lu; Defee, Michael et al. (2013) Kaposi's sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection. J Virol 87:621-35|
Showing the most recent 10 out of 19 publications