Induction of spindle cell morphology in human vascular endothelial cells by human herpesvirus 8-encoded viral FLICE inhibitory protein K13

Matta, Hittu; Surabhi, Rama Mohan; Zhao, Jinshun; Punj, Vasu; Sun, Qing; Schamus, Sandra; Mazzacurati, Lucia; Chaudhary, Preet M.

doi:10.1038/sj.onc.1209931

Cited by 45 publications

(93 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Telomerase-immortalized HUVECs stably expressing vFLIP-ER TAM or a control vector were generated as described previously and were obtained from P.M.C. 23 Cells were treated with 4-OHT (100nM) for induction of gene expression as described previously. 23 Constructs, SiRNA, and transfection Expression vectors for KSHV genes were obtained from J.J.…”

Section: Cell Culturementioning

confidence: 99%

See 1 more Smart Citation

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

Liu¹,

Li²,

Tulpule³

et al. 2010

Blood

View full text Add to dashboard Cite

Kaposi sarcoma–associated herpesvirus (KSHV) infection is essential to the development of Kaposi sarcoma (KS). Notch signaling is also known to play a pivotal role in KS cell survival and lytic phase entrance of KSHV. In the current study, we sought to determine whether KSHV regulates Notch components. KSHV-infected lymphatic endothelial cells showed induction of receptors Notch3 and Notch4, Notch ligands Dll4 and Jagged1, and activated Notch receptors in contrast to uninfected lymphatic endothelial cells. In addition, KSHV induced the expression of endothelial precursor cell marker (CD133) and mural cell markers (calponin, desmin, and smooth muscle alpha actin), suggesting dedifferentiation and trans-differentiation. Overexpression of latency proteins (LANA, vFLIP) and lytic phase proteins (RTA, vGPCR, viral interleukin-6) further supported the direct regulatory capacity of KSHV viral proteins to induce Notch receptors (Notch2, Notch3), ligands (Dll1, Dll4, Jagged1), downstream targets (Hey, Hes), and endothelial precursor CD133. Targeting Notch pathway with γ-secretase inhibitor and a decoy protein in the form of soluble Dll4 inhibited growth of KSHV-transformed endothelial cell line. Soluble Dll4 was also highly active in vivo against KS tumor xenograft. It inhibited tumor cell growth, induced tumor cell death, and reduced vessel perfusion. Soluble Dll4 is thus a candidate for clinical investigation.

show abstract

Section: Cell Culturementioning

confidence: 99%

“…23 Cells were treated with 4-OHT (100nM) for induction of gene expression as described previously. 23 Constructs, SiRNA, and transfection Expression vectors for KSHV genes were obtained from J.J. They include pcDNA3/LANA, pcDNA4/vFLIP, pcDNA3.1/RTA, pcDNA4/vGPCR, and pcDNA3.1/viral interleukin-6 (vIL-6).…”

Section: Cell Culturementioning

confidence: 99%

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

Liu¹,

Li²,

Tulpule³

et al. 2010

Blood

View full text Add to dashboard Cite

show abstract

“…It is intriguing that there is evidence that HHV-8 may induce spindle cell morphology in vitro. 9 Similarly, the role of HHV-8 is well established in Kaposi sarcoma, which shows excessive proliferation of spindle cells thought to have an endothelial cell origin. However, morphologically and immunophenotypically, our case does not bear any resemblance to Kaposi sarcoma and does not appear to be of endothelial origin.…”

Section: Commentmentioning

confidence: 99%

A De Novo Unclassified Malignant Spindle Cell Neoplasm of Liver Allograft

Clevenger

Saxena

Idrees

2014

Archives of Pathology &Amp; Laboratory Medicine

View full text Add to dashboard Cite

Spindle cell neoplasms are rarely reported in liver allografts; most are benign and associated with EpsteinBarr virus infection. We present a case of a malignant spindle cell neoplasm arising in a liver allograft. The patient underwent orthotopic liver transplant for cirrhosis secondary to nonalcoholic steatohepatitis. After 2 years, he presented with vague abdominal complaints. Imaging studies revealed a 10-cm right hepatic lobe mass. The patient underwent right-sided hepatectomy. The tumor displayed areas of broad, relatively hypocellular fascicles, whorls, and perivascular clustering; spindle cells with mild to moderate nuclear pleomorphism; and relatively abundant eosinophilic cytoplasm. Mitotic activity ranged from 2 to 4 mitotic figures per 20 high-power fields. Immunostaining displayed positivity for epithelial membrane antigen, vimentin, CD99, BCL2, cytokeratin, and human herpesvirus 8. Interphase fluorescence in situ hybridization findings were negative for a translocation involving the SS18 gene (18q11). We believe the tumor represents the first reported case of a novel unclassified spindle cell malignant neoplasm in a liver allograft.

show abstract

“…For example, HHV-8 open reading frame (ORF) K13 encodes a viral homolog of FADD-like interferon-converting enzyme inhibitory protein (vFLIP) that prevents death receptor-mediated apoptosis. vFLIP has also been shown to activate the NF-κB (111) and JNK/AP-1 pathways, both of which induce cellular IL-6 expression (113,114). In the context of prostate cancer, increased NF-κB activity and cellular IL-6 signaling have both been shown to be ligandindependent activators of AR expression and transcriptional activity (81,85).…”

Section: Hhv-8 Infection Increases Mapk Erk1/2 Activity Inmentioning

confidence: 99%

“…[187][188][189][190] Herpesvirus -etiological agent for Kaposi's sarcoma (KS), tumor of endothelial and lymphatic origin 101 ERG expression critical for lineage specific differentiation of endothelial cells, angiogenesis and expression of endothelial markers [187][188][189][190] KS lesions composed of "spindle cells," express endothelial and lymphatic markers; virus induces expression of numerous proangiogenic proteins 130 TMPRSS2-ERG gene fusion most prevalent genetic mutation in prostate cancer 27,28 transforms epithelial cells in part by activating MAP kinases 191,192 Virus-encoded proteins activate numerous host cell signaling pathways critical to KS development 130 Oncogenic fusion induces NF-κB activation and inflammation through TLR4 signaling 199 HHV-8 strong inducer of inflammation; activation of NF-κB critical in KS pathology [111][112][113] TMPRSS2-ERG mediates epigenetic regulation through EZH2 140 Viral latency maintained by EZH2 147,148 TMPRSS2-ERG induces epithelialmesenchymal transition [196][197][198] Induces epithelial-mesenchymal transition 149,150 epithelial dedifferentiation and the loss of expression of prostate-defining genes, such as PSA (194,195). This ERG-induced epithelial dedifferentiation occurs as the result of ERG activating EZH2-mediated epigenetic modifications (140).…”

Section: Hhv-8mentioning

confidence: 99%

Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression

Mygatt¹

2012

View full text Add to dashboard Cite

The mechanisms that give rise to androgen-independent prostate cancer (AIPC) are incompletely understood, resulting in a lack of treatment options for this fatal form of the disease. It is believed that most cases of AIPC are the result of constitutive activation of the androgen receptor (AR) pathway, leading us to hypothesize that chronic, prostatic infection could promote cancer progression as a result of pathogen virulence factors activating cell signaling pathways known to induce AR signaling. We found that human

show abstract

Induction of spindle cell morphology in human vascular endothelial cells by human herpesvirus 8-encoded viral FLICE inhibitory protein K13

Cited by 45 publications

References 23 publications

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

A De Novo Unclassified Malignant Spindle Cell Neoplasm of Liver Allograft

Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression

Contact Info

Product

Resources

About