Kaposi's Sarcoma-Associated Herpesvirus Downregulates Transforming Growth Factor β2 To Promote Enhanced Stability of Capillary-Like Tube Formation

DiMaio, Terri A.; Gutierrez, Kimberley D.; Lagunoff, Michael

doi:10.1128/jvi.01696-14

Cited by 21 publications

(20 citation statements)

References 35 publications

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“…Interestingly, our results indicate that TGFβ2, but not TGFβ1, is suppressed by VEGF in HUVECs and that capillary morphogenesis is inhibited by TGFβ2 in these cells, specifically highlighting TGFβ2 as anti-angiogenic in our system. Interestingly, it has been recently shown that KSHV infection of endothelial cells also downregulates TGFβ2 [ 61 ], and given that KSHV upregulates VEGF, our proposed pathway of VEGF-regulation of miR-30b and its downstream effects on TGFβ2 is also supported by this finding. Importantly, our data indicates that cells with higher levels of miR-30b secrete more TGFβ2 and that these cells have higher levels of Smad2 phosphorylation indicating an active autocrine TGFβ signaling pathway.…”

Section: Discussionsupporting

confidence: 77%

MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2

2017

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The importance of microRNA (miRNA) to vascular biology is becoming increasingly evident; however, the function of a significant number of miRNA remains to be determined. In particular, the effect of growth factor regulation of miRNAs on endothelial cell morphogenesis is incomplete. Thus, we aimed to identify miRNAs regulated by pro-angiogenic vascular endothelial growth factor (VEGF) and determine the effects of VEGF-regulated miRNAs and their targets on processes important for angiogenesis. Human umbilical vein endothelial cells (HUVECs) were thus stimulated with VEGF and miRNA levels assessed using microarrays. We found that VEGF altered expression of many miRNA, and for this study focused on one of the most significantly down-regulated miRNA in HUVECs following VEGF treatment, miR-30b. Using specific miRNA mimics, we found that overexpression of miR-30b inhibited capillary morphogenesis in vitro, while depletion of endogenous miR-30b resulted in increased capillary morphogenesis indicating the potential significance of down-regulation of miR-30b as a pro-angiogenic response to VEGF stimulation. MiR-30b overexpression in HUVEC regulated transforming growth factor beta 2 (TGFβ2) production, which led to increased phosphorylation of Smad2, indicating activation of an autocrine TGFβ signaling pathway. Up-regulation of TGFβ2 by miR-30b overexpression was found to be dependent on ATF2 activation, a transcription factor known to regulate TGFβ2 expression, as miR-30b overexpressing cells exhibited increased levels of phosphorylated ATF2 and depletion of ATF2 inhibited miR-30b-induced TGFβ2 expression. However, miR-30b effects on ATF2 were indirect and found to be via targeting of the known ATF2 repressor protein JDP2 whose mRNA levels were indirectly correlated with miR-30b levels. Increased secretion of TGFβ2 from HUVEC was shown to mediate the inhibitory effects of miR-30b on capillary morphogenesis as treatment with a neutralizing antibody to TGFβ2 restored capillary morphogenesis to normal levels in miR-30b overexpressing cells. These results support that the regulation of miR-30b by VEGF in HUVEC is important for capillary morphogenesis, as increased miR-30b expression inhibits capillary morphogenesis through enhanced expression of TGFβ2.

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Section: Discussionsupporting

confidence: 77%

MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2

2017

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“…KSHV microRNAs (miRNAs) are highly expressed during latency and regulate diverse cellular pathways ( 33 ). Results of recent studies showed the association between in vitro angiogenic activities and KSHV miRNAs ( 34 , 35 ). To investigate whether KSHV miRNAs might mediate KSHV-induced angiogenesis in MSCa, we infected them with a mutant virus containing a deletion of a cluster of 10 pre-miRNAs, including pre-miR-K1-9 and -K11 (ΔmiR) ( 36 ) and established a long-term MSCa culture infected with this mutant KSHV (LTC-ΔmiRMSCa).…”

Section: Resultsmentioning

confidence: 99%

Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi’s Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes

Lee

Yuan

Jeon

et al. 2016

mBio

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Kaposi’s sarcoma (KS), a highly angiogenic and invasive tumor often involving different organ sites, including the oral cavity, is caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV). Diverse cell markers have been identified on KS tumor cells, but their origin remains an enigma. We previously showed that KSHV could efficiently infect, transform, and reprogram rat primary mesenchymal stem cells (MSCs) into KS-like tumor cells. In this study, we showed that human primary MSCs derived from diverse organs, including bone marrow (MSCbm), adipose tissue (MSCa), dental pulp, gingiva tissue (GMSC), and exfoliated deciduous teeth, were permissive to KSHV infection. We successfully established long-term cultures of KSHV-infected MSCa, MSCbm, and GMSC (LTC-KMSCs). While LTC-KMSCs had lower proliferation rates than the uninfected cells, they expressed mixtures of KS markers and displayed differential angiogenic, invasive, and transforming phenotypes. Genetic analysis identified KSHV-derived microRNAs that mediated KSHV-induced angiogenic activity by activating the AKT pathway. These results indicated that human MSCs could be the KSHV target cells in vivo and established valid models for delineating the mechanism of KSHV infection, replication, and malignant transformation in biologically relevant cell types.

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“…Infection of endothelial cells with KSHV plays an important role in viral dissemination and paracrine induction of angiogenesis in KS lesions. KSHV-infected endothelial cells share the characteristics of transformed endothelial cells, including cell proliferation, chemotactic migration, and invasion [ 16 , 17 ]. Furthermore, KSHV infection can upregulate various cellular signaling pathways to increase endothelial cell proliferation and vascular permeability during angiogenesis and vasculogenesis [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

KSHV-Mediated Angiogenesis in Tumor Progression

Purushothaman

Uppal

Sarkar

et al. 2016

Viruses

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Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders.

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Kaposi's Sarcoma-Associated Herpesvirus Downregulates Transforming Growth Factor β2 To Promote Enhanced Stability of Capillary-Like Tube Formation

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS),

Cited by 21 publications

References 35 publications

MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2

MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2

Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi’s Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes

KSHV-Mediated Angiogenesis in Tumor Progression

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