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. 2011 Sep 8;118(10):2896-905.
doi: 10.1182/blood-2011-01-330589. Epub 2011 Jun 28.

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

Yu-Hsuan Wu  1 , Tzu-Fang Hu, Yu-Chieh Chen, Ya-Ni Tsai, Yuan-Hau Tsai, Cheng-Chung Cheng, Hsei-Wei Wang
Affiliations
Free article

The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility

Yu-Hsuan Wu et al. Blood. .
Free article

Abstract

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 up-regulated. 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.

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