Mechanistic analysis on KSHV Kaposin B-induced cellular motility

• Main Authors: Ya-Ni Tsai, 蔡雅妮
• Other Authors: Hsei-Wei Wang
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/90125972249061289672

碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 99 === Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV8), is a human oncogenic virus and the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and the multicentric Castleman’s disease. KS is a tumor capable of spreading throughout the body of which pulmonary metastasis is observed clinically. KSHV enhances the migration and invasiveness of primary human umbilical vein endothelial cells (HUVECs) by up-regulating cellular genes including MMP-1, -2 and MMP-9. However, the involving viral proteins and underlying mechanism are still largely unclear. Since KSHV mainly maintains latency after infection, some latent genes may play vital role in the regulation of cell motility. Kaposin B is one of KSHV latent proteins that impairs ARE-mediated mRNA decay, which results in an increase of cytokine release. In this study, we demonstrate that Kaposin B in complex with c-Myc can increase endothelial cell motility through down-regulation of miR-222 expression. As a result, two miR-222 targets, ETS1 and NDRG1, were promineatly up-regulatied. Furthermore, the down-reguation of miR-222 and miR-221 accompanied by the up-regulation of ETS1 and NDRG1 were also found in KSHV-infected lymphatic endothelial cells (LECs) and blood vessel endothelial cells (BECs). ETS1 and NDRG1 are angiogenesis-related genes and may be involved in KSHV-induced endothelial cell motility. Therefore, KSHV may induce angiogenesis and tumor metastasis through c-Myc, and through altering the expression of cellular microRNA (miRNA) and its downstream targets. Targeting KSHV-regulated cellular miRNAs or their downstream targets may represent a novel approach for treating KSHV-associated neoplasia or pathogenic (lymph)angiogenesis.