Kaposi's sarcoma herpesvirus-induced endothelial cell reprogramming supports viral persistence and contributes to Kaposi's sarcoma tumorigenesis

Chen

Journal of Medical Virology

et al. 2018

Background and purpose Kaposi's sarcoma–associated herpes virus (KSHV) vIL‐6 is sufficient to induce lymphatic reprogramming of vascular endothelial cells, which is a key event in Kaposi's sarcoma (KS) development. This study was aimed to investigate the effect of Chinese herb oroxylin A on lymphatic reprogramming and neovascularization by KSHV vIL‐6 in vitro and in vivo. Methods The lymphatic‐phenotype endothelial cell line was generated by lentiviral KSHV vIL‐6 infection. Cell viability and apoptosis were determined by MTT assay or flow cytometry with annexin V/propidium iodide staining. Migration, invasion, and neovascularization of the vIL‐6‐expressing lymphatic‐phenotype endothelial cells were determined by wound healing assay, transwell chamber assay, microtubule formation assay, and chick chorioallantoic membrane assay, respectively. Quantitative polymerase chain reaction and Western blot analysis were used to test the expression of Prox1, VEGFR3, podoplanin, LYVE‐1, and PPARγ in cells. Co‐localization of Prox1 and PPARγ was determined by immunofluorescence. Ubiquitination of Prox1 was detected by in vivo ubiquitination assay. Results The lymphatic‐phenotype endothelial cell line expressing KSHV vIL‐6 was successfully generated. Oroxylin A induced cellular invasion abrogation, apoptosis induction, and neovascularization inhibition of the vIL‐6‐expressing endothelial cells. Mechanically, oroxylin A elevated PPARγ expression, which in turn interacted with and facilitated Prox1 to undergo ubiquitinational degradation, and subsequently leads to VEGFR3, LYVE‐1, and podoplanin reduction. Conclusion Through modulating PPARγ/Prox1 axis, oroxylin A inhibits lymphatic reprogramming and neovascularization of KSHV vIL‐6. Thus, oroxylin A may serve as a candidate for the treatment of KS as well as other aggressive angiomas.

mentioning

confidence: 60%

“…Lymphatic reprogramming plays a pivotal role in KS development . In the present study, we successfully established a lymphatic‐phenotype endothelial cell line by transduction of KSHV vIL‐6 gene into the HUVECs.…”

Section: Discussionmentioning

confidence: 93%

Oroxylin A inhibits Kaposi's sarcoma‐associated herpes virus (KSHV) vIL‐6–mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis

Chen

Journal of Medical Virology

et al. 2018

“…KS is the most common cancer among AIDS patients and a frequent malignancy in Sub-Saharan Africa 1 . KS presents with skin lesions that progress from patch to plaque and ultimately to nodular tumours; in advanced disease visceral involvement is also seen 2, 3 . The histopathological hallmark of KS is the presence of KSHV-positive spindle cells (SC), the tumour cells of KS 2, 3 .…”

Section: Mainmentioning

confidence: 99%

“…KS presents with skin lesions that progress from patch to plaque and ultimately to nodular tumours; in advanced disease visceral involvement is also seen 2, 3 . The histopathological hallmark of KS is the presence of KSHV-positive spindle cells (SC), the tumour cells of KS 2, 3 . The cell of origin of SC has been debated for two decades 3 .…”

Section: Mainmentioning

confidence: 99%

See 1 more Smart Citation

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli

Elbasani

Nurminen

et al. 2019

Preprint

Self Cite

27Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection 28 and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency 29 in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with 30 high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, 31 SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique 32 KSHV infection program. We found that these factors were co-expressed in KS tumours with the 33 viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent 34 mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition 35 significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator 36 of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces 37 KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in 38 the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate 39 the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and 40 introduce SOX18 inhibition as a potential, novel therapeutic modality for KS. 41 42 43 KEYWORDS 44 Kaposi sarcoma, KSHV, herpesvirus, K8.1, transcription factors, PROX1, SOX18, lymphatic 45 endothelial cells, viral genome replication, viral reactivation. 46 47 3 MAIN 48Kaposi sarcoma (KS) is an angiogenic endothelial tumour caused by KS herpesvirus (KSHV). KS is 49 the most common cancer among AIDS patients and a frequent malignancy in Sub-Saharan Africa 1 . 50 KS presents with skin lesions that progress from patch to plaque and ultimately to nodular tumours; 51 in advanced disease visceral involvement is also seen 2,3 . The histopathological hallmark of KS is the 52 presence of KSHV-positive spindle cells (SC), the tumour cells of KS 2,3 . The cell of origin of SC has 53 been debated for two decades 3 . The prevailing hypothesis suggests lymphatic endothelial origin, 54 although blood endothelial cells or mesenchymal cells are also candidates 1,4 . In vitro, latency is the 55 default replication program in KSHV-infected cells with undetectable levels of lytic genes expressed. 56 However, KSHV infection of lymphatic, but not blood, endothelial cells (LEC and BEC) leads to a 57 unique infection program characterized by high KSHV genome copies, spontaneous lytic gene 58 expression and release of infectious virus 5-8 . 59 60 During embryonic development, LEC precursors originate from COUPTF2/SOX18 double-positive 61 BECs that physically separate from the cardinal vein to establish a primary lymphatic vascular plexus. 62 In this process, COUPTF2 and SOX18 drive the expression of PROX1 thereby orchestrating LEC 63 differentiation 9,10 . Here, we explored the role of these transcription factors (TF), instrumental for 64 establishment...

Skin Health and Disease

Paraneoplastic scleroderma in Kaposi's sarcoma: Report of two cases

Ali

Belcadi

Znati

et al. 2023

Kaposi's sarcoma (KS) is a proliferative and multifocal disease with a double vascular and fibroblastic cell component, of mucocutaneous and visceral expression. It is a multifocal tumoral process, hyperplastic in nature without metastatic potential, induced by the human herpes virus 8 (HHV8). Paraneoplastic syndromes (PS) in KS are rare, with only a small number of cases reported and we have found no previous descriptions of a paraneoplastic scleroderma in KS in the literature. We report the cases of two patients with this atypical PS.