Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma.
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.
Department of Oncology, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Yueyu
Y
Cao
Department of Pediatrics, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Jing
J
Qiao
Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA 70112, USA.
Zhen
Z
Lin
Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA 70112, USA.
Jovanny
J
Zabaleta
Department of Oncology, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Genetics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA 70112, USA.
Lu
L
Dai
Department of Oncology, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Genetics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA 70112, USA.
Zhiqiang
Z
Qin
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D002518:Ceramides / Q000494:pharmacology*; D019288:Herpesvirus 8, Human / Q000502:physiology; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000378:metabolism* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D002518:Ceramides; D012333:RNA, Messenger
KSHV; microRNA; primary effusion lymphoma; tumor suppressor gene