| Summary: | 博士 === 國立陽明大學 === 微生物及免疫學研究所 === 99 === Angiogenesis and lymphangiogenesis refer to the processes involving the formation of new blood vessels and new lymphatic vessels, respectively. Both (lymph)angiogenesis are not only necessary for normal and vital processes in growth and development but also required for invasive tumor progression and metastasis. MicroRNAs have emerged as master regulators of cancer-related events. MicroRNA dysregulation also occurs in Kaposi’s sarcoma (KS). Exploring the roles of KS-associated microRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. Here we show that KSHV, the etiological agent of KS, induces global microRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, while miR-31 is up-regulated. Both LANA and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of EC migration. In contrast, miR-31 stimulates EC migration, and depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative microRNA 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, while a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple microRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated microRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.
|
|---|
