Abstract
Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides “killing” PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors.
Highlights
Primary effusion lymphoma (PEL) is a rare B-cell malignancy that originates from B cells latently infected with Kaposi’s sarcoma-associated herpesvirus (KSHV, known as human herpesvirus-8, HHV8)
Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis
DhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression
Summary
Primary effusion lymphoma (PEL) is a rare B-cell malignancy that originates from B cells latently infected with Kaposi’s sarcoma-associated herpesvirus (KSHV, known as human herpesvirus-8, HHV8). Bioactive sphingolipids, including ceramides and S1P, act as signaling molecules that regulate apoptosis www.impactjournals.com/oncotarget and tumor cell survival [5]. The underlying mechanisms for these exogenous ceramides “killing” PEL cells still require further investigation, which will be helpful to better understand PEL pathogenesis and identify more potential therapeutic targets. We used the Illumina microarray to determine the altered gene profile in one KSHV+ PEL cell-line, BCBL-1, exposure to dhC16-Cer. We found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16Cer treated BCBL-1 cells. We found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16Cer treated BCBL-1 cells One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16Cer induced PEL cell cycle arrest. DhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression
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