KSHV Regulation of Fibulin-2 in Kaposi's Sarcoma

Abstract

Kaposi's sarcoma is an angioproliferative tumor caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection of vascular endothelial cells. Fibulins, proteins that associate with extracellular matrix (ECM) proteins, may have both tumor-suppressive and oncogenic activities. We found that the expression of fibulin-2 protein and mRNA were decreased 50-fold and 26-fold, respectively, in 10-day KSHVinfected dermal microvascular endothelial cells (DMVEC). Using quantitative RT-PCR, we found a fivefold and 25-fold decrease of fibulin-2 extracellular matrix binding partners, fibronectin and tropoelastin, respectively. Time-course transcriptional analyses over 10 days showed that in addition to that of fibulin-2, expression of fibulins 3 and 5 was decreased in KSHVinfected DMVEC, fibulins 1C/1D were increased, and fibulins 4, 6, and 7 were unchanged. KSHV latencyassociated nuclear antigen (LANA) transcription levels rose consistently over the same period. Addition of recombinant fibulin-3 or -5 for 48 hours to 10-day KSHV-infected cells caused a suppression of KSHVinduced vascular endothelial growth factor (VEGF) protein and mRNA levels. Recombinant fibulin-3 also significantly reduced VEGF receptor 3 expression. In pleural effusion lymphoma cell lines that express variable levels of KSHV lytic replication, we observed no detectable fibulin-2 or -5 expression. Finally, fibulin-2 expression was decreased in tissue microarrays from KSHV-infected, LANA-positive patient cells as compared to that in patient nontumor controls. Understanding the interactions between KSHV and the fibulins may lead to the development of novel therapies for treatment of Kaposi's sarcoma.

Site-Specific Association with Host and Viral Chromatin by Kaposi's Sarcoma-Associated Herpesvirus LANA and Its Reversal during Lytic Reactivation

“…Figure 6C shows a succinct list of the most regulated genes in LEC-219s identified by our RNA-seq approach. The host genes previously reported to be modulated in KSHV-infected endothelial cells are depicted in bold (72,(75)(76)(77)(78)(79). The full list of KSHV-regulated genes is available in Data Set S3 in the supplemental material.…”

WITHDRAWN: Fibulin 2, a tyrosine o-sulfated protein, is up-regulated following retinal detachment

“…Fibulin 1 disruptions cause synpolydactyly in humans, which is characterized by malformation of distal limbs due to bone fusion (12). Fibulin 2 is down-regulated in breast cancer, colorectal cancer, lung cancer, Kaposi's sarcoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and childhood acute lymphoblastic leukemia (13)(14)(15)(16)(17). The down-regulation of fibulin 2 in these cancers is either due to methylation of its promoter, gene deletion, or simply down-regulation of the levels of protein (13,14).…”

Kaposi's sarcoma‐associated herpesvirus (KSHV)‐encoded microRNAs promote matrix metalloproteinases (MMPs) expression and pro‐angiogenic cytokine secretion in endothelial cells

“…Angiogenesis is critical for the growth of solid tumors and some hematological malignancies . Studies have demonstrated that VEGF/VEGFR‐related pathways are the most relevant regulators of neoangiogenesis, vasculogenesis, and recruitment of endothelial progenitor cells . VEGF is expressed at an elevated level by KSHV‐infected endothelial cells and KS spindle cells and is a key mediator of angiogenesis and vascular permeability in KS lesions .…”