期刊
BLOOD
卷 118, 期 10, 页码 2896-2905出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-01-330589
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资金
- National Research Program for Genomic Medicine of the National Science Council at the Veterans General Hospital-Yang Ming Genome Research Center
- National Science Council [NSC99-3111-B-010-003, NSC98-2320-B-010-020-MY3, NSC 99-2911-I-009-101]
- Yen Tjing Lin Medical Foundation [CI-98-11]
- National Health Research Institutes [NHRI-EX99-9704BI]
- Department of Health [CCMP99-RD-063]
- Taipei Veterans General Hospital [V100E2-011, DOH100-TD-C-111-007]
- MacKay Memorial Hospital [MMH-HB-100-01]
- Yang-Ming University (Ministry of Education)
miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is upregulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph) angiogenesis. (Blood. 2011; 118(10): 2896-2905)
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