Kaposi Sarcoma


Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Endothelial Cells
  • Transfection
  • HLA-DR Antigens
  • Herpesviridae Infections
  • Gene Expression Regulation
  • MART1
  • HIV Infections
  • Genotype
  • Amino Acid Sequence
  • Kaposi Sarcoma
  • Gene Expression Profiling
  • Cancer DNA
  • Soft Tissue Cancers
  • Up-Regulation
  • Cell Line
  • IL12A
  • Interleukin-6
  • DNA, Viral
  • IL4
  • Base Sequence
  • Polymerase Chain Reaction
  • Promoter Regions
  • Mutation
  • Genetic Predisposition
  • Alleles
  • HLA-DQB1
  • Gene Expression Regulation, Viral
  • Oncogenes
  • MicroRNAs
  • Skin Cancer
  • Immunohistochemistry
  • Case-Control Studies
  • Herpesvirus 8, Human
  • CD40
  • microRNA mir-1297
  • Molecular Sequence Data
  • Cancer Gene Expression Regulation
  • Polymorphism
  • Acquired Immunodeficiency Syndrome
  • Proto-Oncogene Proteins
  • HIV-1
  • Risk Factors
  • Messenger RNA
  • AIDS-Related Opportunistic Infections
  • FGF3
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (17)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

CD40 20q12-q13.2 p50, Bp50, CDW40, TNFRSF5 -CD40 and Kaposi's Sarcoma
FGF3 11q13.3 INT2, HBGF-3 -FGF3 and Kaposi Sarcoma
CCR5 3p21.31 CKR5, CCR-5, CD195, CKR-5, CCCKR5, CMKBR5, IDDM22, CC-CKR-5 -CCR5 and Kaposi Sarcoma
IKBKB 8p11.2 IKK2, IKKB, IMD15, NFKBIKB, IKK-beta -IKBKB and Kaposi Sarcoma
IL4 5q31.1 BSF1, IL-4, BCGF1, BSF-1, BCGF-1 -IL4 and Kaposi Sarcoma
HLA-DQA1 6p21.3 CD, GSE, DQ-A1, CELIAC1, HLA-DQA -HLA-DQA1 and Kaposi Sarcoma
HLA-DRA 6p21.3 MLRW, HLA-DRA1 -HLA-DRA and Kaposi Sarcoma
IL1B 2q14 IL-1, IL1F2, IL1-BETA -IL1B and Kaposi Sarcoma
IL1A 2q14 IL1, IL-1A, IL1F1, IL1-ALPHA -IL1A and Kaposi Sarcoma
FGF4 11q13.3 HST, KFGF, HST-1, HSTF1, K-FGF, HBGF-4 -FGF4 and Kaposi Sarcoma
IL12A 3q25.33 P35, CLMF, NFSK, NKSF1, IL-12A -IL12A and Kaposi Sarcoma
MIR1297 13 MIRN1297, mir-1297, hsa-mir-1297 -MIRN1297 microRNA, human and Kaposi Sarcoma
IL13 5q31 P600, IL-13 -IL13 and Kaposi Sarcoma
FCGR3A 1q23 CD16, FCG3, CD16A, FCGR3, IGFR3, IMD20, FCR-10, FCRIII, FCGRIII, FCRIIIA -FCGR3A and Kaposi Sarcoma
HLA-DQB1 6p21.3 IDDM1, CELIAC1, HLA-DQB -HLA-DQB1 and Kaposi Sarcoma
APOE 19q13.2 AD2, LPG, APO-E, LDLCQ5 -APOE and Kaposi Sarcoma
MLANA 9p24.1 MART1, MART-1 -MLANA and Kaposi Sarcoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Tozetto-Mendoza TR, Ibrahim KY, Tateno AF, et al.
Genotypic distribution of HHV-8 in AIDS individuals without and with Kaposi sarcoma: Is genotype B associated with better prognosis of AIDS-KS?
Medicine (Baltimore). 2016; 95(48):e5291 [PubMed] Free Access to Full Article Related Publications
AIDS-associated Kaposi's sarcoma (AIDS-KS) caused by human herpes virus 8 (HHV-8) is the most severe and resistant form of KS tumor. Our aim was to verify whether there is an association between HHV-8 variability and development of AIDS-KS in Brazil by comparing the HHV-8 variability between individuals without and with KS. Saliva samples and blood, when available, were analyzed by polymerase chain reaction (PCR) techniques for detection of the fragments of ORF K1 of HHV-8, which were then genotyped and analyzed regarding the genetic variability. Our study described 106 positive cases for HHV-8 in the saliva from 751 AIDS patients without previous KS. In addition, we performed a phylogenetic analysis of HHV-8 in 34 of the 106 AIDS patients without KS and in 33 of the 37 patients with active KS. The distribution of HHV-8 genotypes A, B, C, and F in AIDS individuals was indistinguishable by comparing non-KS and KS groups, as well as regarding ethnicity. Considering the KS group, genotype B was associated with better prognosis of KS tumor. Interestingly, we found a particular profile of diversity within clade C and 2 recombinant patterns of HHV-8 in the saliva of AIDS individuals without KS. We emphasize the need to achieve standard genotyping protocol for ORF K1 amplification, thus allowing for substantial detection of HHV-8 variants. Our findings can shed light on the role of HHV-8 variability in the pathogenesis of AIDS-KS.

Yang H, Lu QL, Wu XJ, et al.
Association of genetic variations in miR-146a rs2910164 and miR-149 rs11614913 with the development of classic Kaposi sarcoma.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Classic Kaposi sarcoma is a type of vascular proliferative inflammatory disease. Previous studies have reported significant associations between microRNAs expression and the development of classic Kaposi sarcoma. Here, we conducted a case-control study to investigate the association between miR-146a and miR-149 genetic polymorphisms and risk of classic Kaposi sarcoma in a Chinese population. Both classic Kaposi sarcoma patients and healthy controls were recruited between December 2013 and October 2015. Genotyping of miR-146a and miR-149 was performed by polymerase chain reaction-coupled with restriction fragment length polymorphism. Results showed that the GG genotype of miR-146a was associated with increased risk to classic Kaposi sarcoma (OR = 6.00, 95%CI = 1.19-30.12), as compared with the CC genotype. In the recessive model, we found that the GG genotype carried a 4.55-fold increased risk to classic Kaposi sarcoma as compared with the CC + CG genotype (OR = 2.06, 95%CI = 1.04-20.29). In conclusion, our study demonstrated that miR-146a, but not miR-149 polymorphism, is associated with risk to classic Kaposi sarcoma in the Chinese population.

Olp LN, Jeanniard A, Marimo C, et al.
Whole-Genome Sequencing of Kaposi's Sarcoma-Associated Herpesvirus from Zambian Kaposi's Sarcoma Biopsy Specimens Reveals Unique Viral Diversity.
J Virol. 2015; 89(24):12299-308 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS). Both KSHV and KS are endemic in sub-Saharan Africa where approximately 84% of global KS cases occur. Nevertheless, whole-genome sequencing of KSHV has only been completed using isolates from Western countries-where KS is not endemic. The lack of whole-genome KSHV sequence data from the most clinically important geographical region, sub-Saharan Africa, represents an important gap since it remains unclear whether genomic diversity has a role on KSHV pathogenesis. We hypothesized that distinct KSHV genotypes might be present in sub-Saharan Africa compared to Western countries. Using a KSHV-targeted enrichment protocol followed by Illumina deep-sequencing, we generated and analyzed 16 unique Zambian, KS-derived, KSHV genomes. We enriched KSHV DNA over cellular DNA 1,851 to 18,235-fold. Enrichment provided coverage levels up to 24,740-fold; therefore, supporting highly confident polymorphism analysis. Multiple alignment of the 16 newly sequenced KSHV genomes showed low level variability across the entire central conserved region. This variability resulted in distinct phylogenetic clustering between Zambian KSHV genomic sequences and those derived from Western countries. Importantly, the phylogenetic segregation of Zambian from Western sequences occurred irrespective of inclusion of the highly variable genes K1 and K15. We also show that four genes within the more conserved region of the KSHV genome contained polymorphisms that partially, but not fully, contributed to the unique Zambian KSHV whole-genome phylogenetic structure. Taken together, our data suggest that the whole KSHV genome should be taken into consideration for accurate viral characterization.
IMPORTANCE: Our results represent the largest number of KSHV whole-genomic sequences published to date and the first time that multiple genomes have been sequenced from sub-Saharan Africa, a geographic area where KS is highly endemic. Based on our new sequence data, it is apparent that whole-genome KSHV diversity is greater than previously appreciated and differential phylogenetic clustering exists between viral genomes of Zambia and Western countries. Furthermore, individual genes may be insufficient for KSHV genetic characterization. Continued investigation of the KSHV genetic landscape is necessary in order to effectively understand the role of viral evolution and sequence diversity on KSHV gene functions and pathogenesis.

Goedert JJ, Martin MP, Vitale F, et al.
Risk of Classic Kaposi Sarcoma With Combinations of Killer Immunoglobulin-Like Receptor and Human Leukocyte Antigen Loci: A Population-Based Case-control Study.
J Infect Dis. 2016; 213(3):432-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Kaposi sarcoma (KS) is a complication of KS-associated herpesvirus (KSHV) infection. Other oncogenic viral infections and malignancies are associated with certain HLA alleles and their natural killer (NK) cell immunoglobulin-like receptor (KIR) ligands. We tested whether HLA-KIR influences the risk of KSHV infection or KS.
METHODS: In population-based case-control studies, we compared HLA class I and KIR gene frequencies in 250 classic (non-AIDS) KS cases, 280 KSHV-seropositive controls, and 576 KSHV-seronegative controls composing discovery and validation cohorts. Logistic regression was used to calculate sex- and age-adjusted odds ratios (ORs) and 95% confidence intervals.
RESULTS: In both the discovery and validation cohorts, KS was associated with HLA-A*11:01 (adjusted OR for the combined cohorts, 0.4; P = .002) and HLA-C*07:01 (adjusted OR, 1.6; P = .002). Consistent associations across cohorts were also observed with activating KIR3DS1 plus HLA-B Bw4-80I and homozygosity for HLA-C group 1. With KIR3DS1 plus HLA-B Bw4-80I, the KSHV seroprevalence was 40% lower (adjusted OR for the combined cohorts, 0.6; P = .01), but the KS risk was 2-fold higher (adjusted OR, 2.1; P = .002). Similarly, the KSHV seroprevalence was 40% lower (adjusted OR, 0.6; P = .01) but the KS risk 80% higher with HLA-C group 1 homozygosity (adjusted OR, 1.8; P = .005).
CONCLUSIONS: KIR-mediated NK cell activation may decrease then risk of KSHV infection but enhance KSHV dissemination and progression to KS if infection occurs.

Tan X, Gao Y, Nan Y, et al.
Cellular MicroRNA Let-7a Suppresses KSHV Replication through Targeting MAP4K4 Signaling Pathways.
PLoS One. 2015; 10(7):e0132148 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the etiologic agent of KS, the most common AIDS-related malignancy. The majority of KS tumor cells harbor latent KSHV virus but only a small percentage undergoes spontaneous lytic replication. Viral reactivation from latency is crucial for the pathogenesis and development of KS, but the cellular mechanisms underlying the switch between viral latency and replication are not well understood.
METHODS: The level of let-7 miRNAs and MAP4K4 in KSHV infected 293T cells were quantified by real-time PCRs. Let-7 expression was silenced by the miRNA sponge technique. In let-7a transfected 293T cells, the expression of MAP4K4 was measured by real-time PCR and western blot. Luciferease expression was employed to examine the effect of let-7a on the 3'-untranslated region (UTR) of the MAP4K4 gene in 293T cells. Real-time PCR was used to quantify the KSHV copy numbers in BC-3 cells in which the expression of let-7a and/or MAP4K4 were altered. Finally, ERK, JNK and p38 protein production and their phosphorylation status were detected by western blots in let-7a or MAP4K4 transfected BCBL-1 cells.
RESULTS: The expression of microRNA let-7 was dramatically decreased in KSHV infected 293T cells, but that of MAP4K4 was increased significantly. Let-7a is physically associated with and targets the MAP4K4 3'UTR, and inhibits MAP4K4 expression at both mRNA and protein levels. MAP4K4 stimulates KSHV reactivation from latency, whereas let-7a inhibits the function of MAP4K4 by reversing the function of MAP4K4 on JNK, phospho-JNK and phospho-ERK1/2 levels.
CONCLUSION: Our results establish that let-7a specifically suppresses MAP4K4 expression, and further inhibits KSHV reactivation by interfering with the function of MAP4K4 on the MAPK pathway, highlighting let-7a as a potential treatment for KS.

Yuan D, XiuJuan W, Yan Z, et al.
Use of X-Chromosome Inactivation Pattern to Analyze the Clonality of 14 Female Cases of Kaposi Sarcoma.
Med Sci Monit Basic Res. 2015; 21:116-22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Kaposi sarcoma (KS) has features of both neoplastic growth and hyperplastic proliferation. It is the most common tumor seen in patients with HIV infection. Whether KS is a real tumor or a benign hyperplastic disease is not known.
MATERIAL AND METHODS: Tissues from KS and cutaneous hemangioma lesion DNA were extracted, and then digested with methylation-sensitive restriction endonuclease HpaII. Human androgen receptor gene (HUMARA) was amplified with PCR method and the product was separated on 10% denaturing polyacrylamide gels and stained with ethylene dibromide (EB) to show the polymorphism of HUMARA. Phosphoglycerate kinase (PGK) was amplified and the product was digested by BStXI, agarose gel and EB stained to show the polymorphism of PGK. Finally, we analyzed the clonality of KS.
RESULTS: In the 14 patients with KS, heterozygosity of the HUMARA gene was observed in 12 (85.7%) cases. Loss of heterozygosity of HUMARA gene on X-chromosome (without HpaII digestion there were 2 bands, after HpaII digestion there were just 1 of the bands), representing monoclonal origin, was present in 11 cases of Kaposi sarcoma. Heterozygosity of the PGK gene was observed in 5 (35.7%) cases, which all represent monoclonal origin. There was no significant difference according to country, stage, or HIV and HHV-8 (P>0.05).
CONCLUSIONS: The current findings suggest that Kaposi sarcoma is a clonal neoplasm, not a reactive proliferation.

Viollet C, Davis DA, Reczko M, et al.
Next-Generation Sequencing Analysis Reveals Differential Expression Profiles of MiRNA-mRNA Target Pairs in KSHV-Infected Cells.
PLoS One. 2015; 10(5):e0126439 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma associated herpesvirus (KSHV) causes several tumors, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). Cellular and viral microRNAs (miRNAs) have been shown to play important roles in regulating gene expression. A better knowledge of the miRNA-mediated pathways affected by KSHV infection is therefore important for understanding viral infection and tumor pathogenesis. In this study, we used deep sequencing to analyze miRNA and cellular mRNA expression in a cell line with latent KSHV infection (SLKK) as compared to the uninfected SLK line. This approach revealed 153 differentially expressed human miRNAs, eight of which were independently confirmed by qRT-PCR. KSHV infection led to the dysregulation of ~15% of the human miRNA pool and most of these cellular miRNAs were down-regulated, including nearly all members of the 14q32 miRNA cluster, a genomic locus linked to cancer and that is deleted in a number of PEL cell lines. Furthermore, we identified 48 miRNAs that were associated with a total of 1,117 predicted or experimentally validated target mRNAs; of these mRNAs, a majority (73%) were inversely correlated to expression changes of their respective miRNAs, suggesting miRNA-mediated silencing mechanisms were involved in a number of these alterations. Several dysregulated miRNA-mRNA pairs may facilitate KSHV infection or tumor formation, such as up-regulated miR-708-5p, associated with a decrease in pro-apoptotic caspase-2 and leukemia inhibitory factor LIF, or down-regulated miR-409-5p, associated with an increase in the p53-inhibitor MDM2. Transfection of miRNA mimics provided further evidence that changes in miRNAs are driving some observed mRNA changes. Using filtered datasets, we also identified several canonical pathways that were significantly enriched in differentially expressed miRNA-mRNA pairs, such as the epithelial-to-mesenchymal transition and the interleukin-8 signaling pathways. Overall, our data provide a more detailed understanding of KSHV latency and guide further studies of the biological significance of these changes.

Jalilvand S, Shoja Z, Marashi SM, et al.
Mitochondrial haplogroups and control region polymorphisms in Kaposi's sarcoma patients.
J Med Virol. 2015; 87(9):1608-15 [PubMed] Related Publications
Inflammation and reactive oxygen species (ROS) production have recently considered as key mechanisms in the pathogenesis of Kaposi's sarcoma (KS). Since mitochondria are the major source of ROS production, this organelle may play a main role in KS development. However, there are no studies on mtDNA variations and haplogroups in this area. The focus of this study was to investigate the mtDNA variants and haplogroups in KS patients and their relationship to tumor development. To address this, we have genotyped mtDNA in 45 Iranian KS patients and 48 age and sex-matched Iranian controls. A strong positive correlation was observed between UK cluster and decreased risk of KS. Our results suggest that the UK cluster might be a protective haplogroup for KS development. It is probably superhaplogroup UK, with lower ATP and ROS production, may prevent KSHV reactivation from latent to lytic phase that is essential for KS development.

Cordiali-Fei P, Trento E, Giovanetti M, et al.
Analysis of the ORFK1 hypervariable regions reveal distinct HHV-8 clustering in Kaposi's sarcoma and non-Kaposi's cases.
J Exp Clin Cancer Res. 2015; 34:1 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Classical Kaposi's Sarcoma (cKS) is a rare vascular tumor, which develops in subjects infected with Human Herpesvirus-8 (HHV-8). Beside the host predisposing factors, viral genetic variants might possibly be related to disease development. The aim of this study was to identify HHV-8 variants in patients with cKS or in HHV-8 infected subjects either asymptomatic or with cKS-unrelated cutaneous lymphoproliferative disorders.
METHODS: The VR1 and VR2 regions of the ORF K1 sequence were analyzed in samples (peripheral blood and/or lesional tissue) collected between 2000 and 2010 from 27 subjects with HHV-8 infection, established by the presence of anti-HHV-8 antibodies. On the basis of viral genotyping, a phylogenetic analysis and a time-scaled evaluation were performed.
RESULTS: Two main clades of HHV-8, corresponding to A and C subtypes, were identified. Moreover, for each subtype, two main clusters were found distinctively associated to cKS or non-cKS subjects. Selective pressure analysis showed twelve sites of the K1 coding gene (VR1 and VR2 regions) under positive selective pressure and one site under negative pressure.
CONCLUSION: Thus, present data suggest that HHV-8 genetic variants may influence the susceptibility to cKS in individuals with HHV-8 infection.

Aavikko M, Kaasinen E, Nieminen JK, et al.
Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma.
J Infect Dis. 2015; 211(11):1842-51 [PubMed] Related Publications
BACKGROUND: Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection.
METHODS: We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family.
RESULTS: We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C>T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon γ production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations.
CONCLUSIONS: Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.

Tudor S, Giza DE, Lin HY, et al.
Cellular and Kaposi's sarcoma-associated herpes virus microRNAs in sepsis and surgical trauma.
Cell Death Dis. 2014; 5:e1559 [PubMed] Free Access to Full Article Related Publications
Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukin's secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation.

Zhang J, Wang S, Lu L, Wei G
MiR99a modulates MMP7 and MMP13 to regulate invasiveness of Kaposi's sarcoma.
Tumour Biol. 2014; 35(12):12567-73 [PubMed] Related Publications
Matrix metalloproteinases (MMPs) and microRNAs (miRNAs) are associated with Kaposi's sarcoma (KS) tumorigenesis. To date, the molecular basis underlying crosstalk of MMPs and miRNAs in KS remains unexplored. From the resected KS samples, we detected significant correlation of miRNA99a (miR99a), with MMP7 and MMP13, but not with MMP9. To define whether a causal link exists, we used a human KS line, SLK, to study the molecular basis of miR99a and activation of MMP7, MMP9, and MMP13. We found that overexpression of miR99a in SLK cells decreased MMP7 and MMP13, but not MMP9. Similarly, MiR99a inhibition in SLK cells activated MMP7 and MMP13, but did not affect expression of MMP9. These data suggest that MMP7 and MMP13 seem to be regulated by miR99a, while MMP9 seems to be regulated in a miR99a-independent manner. Inhibition of PI3k/Akt signaling pathway significantly abolished the effect of miR99a-knockdown on MMP7, but not MMP13 activation, while inhibition of ERK/MAPK signaling pathway significantly abolished the effect of miR99a-knockdown on MMP13, but not MMP7 activation. Taken together, our data suggest that miR99a inhibits MMP7 and MMP13 through PI3k/Akt and ERK/MAPK signaling pathway, respectively, in KS. Thus, miR99a, MMP7, and MMP13 appear to be promising therapeutic targets for preventing the metastasis of KS.

Aissani B, Boehme AK, Wiener HW, et al.
SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.
Genes Immun. 2014; 15(6):424-9 [PubMed] Free Access to Full Article Related Publications
The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi's sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and human herpes virus-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls. We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a fourfold increase of risk (odds ratio (OR)=4.09; 95% confidence interval (CI)=1.90-8.80; P=0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI=2.54-43.6; P=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120-kb-long haplotype (OR=1.52; 95% CI=1.01-2.28; P=0.047) formed by rs7029 A>G (GPANK1 3' untranslated region), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 read through) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.

Tan X, Li D, Wang X, et al.
Claudin-2 downregulation by KSHV infection is involved in the regulation of endothelial barrier function.
J Cutan Pathol. 2014; 41(8):630-9 [PubMed] Related Publications
BACKGROUND: Kaposi sarcoma (KS), caused by the infection of Kaposi sarcoma-associated herpesvirus (KSHV), is a disease manifested mainly by dark purple skin and mouth nodules. Cancer care studies showed that co-infection of KSHV and human immunodeficiency virus (HIV) was able to increase the patients' survival, but the underlying mechanisms are still elusive.
METHODS: To understand the mechanism underlying the prolonged survival in KSHV-HIV co-infected patients, we performed microarray analysis on RNA extracted from biopsies from KS tumors and adjacent healthy tissues in four KS patients. Subsequently, we performed hierarchical clustering, gene ontology (GO) and ingenuity pathway analysis. We then characterized the roles of tight junction protein claudin-2 in the endothelial barrier function.
RESULTS: Three hundred and forty-three differentially expressed genes were identified, of which 246 genes exhibited significantly increased expression in the tumor compared to the adjacent healthy tissue and 97 genes showed downregulated expression, including claudin-2. Knockdown of claudin-2 in cultured endothelial cells enhances barrier function by altering the charge selectivity, but not the size selectivity.
CONCLUSION: Claudin-2 expression is decreased in KS tumors from patients co-infected with KSHV and HIV. Decreased claudin-2 enhances endothelial barrier function and may play a role in the prolonged survival of patients with KSHV and HIV co-infection.

Schroeder U, Lauten M, Stichtenoth G, et al.
Laryngomalacia and complicated, life-threatening mTOR-positive Kaposiform hemangioendothelioma cured by Supraglottoplasty and sirolimus.
Klin Padiatr. 2014; 226(6-7):362-8 [PubMed] Related Publications
The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE.

Chudasama P, Konrad A, Jochmann R, et al.
Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53-mediated apoptosis.
Oncogene. 2015; 34(5):639-49 [PubMed] Related Publications
The tumor suppressor p53 is a central regulatory molecule of apoptosis and is commonly mutated in tumors. Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies express wild-type p53. Accordingly, KSHV encodes proteins that counteract the cell death-inducing effects of p53. Here, the effects of all KSHV genes on the p53 signaling pathway were systematically analyzed using the reversely transfected cell microarray technology. With this approach we detected eight KSHV-encoded genes with potent p53 inhibiting activity in addition to the previously described inhibitory effects of KSHV genes ORF50, K10 and K10.5. Interestingly, the three most potent newly identified inhibitors were KSHV structural proteins, namely ORF22 (glycoprotein H), ORF25 (major capsid protein) and ORF64 (tegument protein). Validation of these results with a classical transfection approach showed that these proteins inhibited p53 signaling in a dose-dependent manner and that this effect could be reversed by small interfering RNA-mediated knockdown of the respective viral gene. All three genes inhibited p53-mediated apoptosis in response to Nutlin-3 treatment in non-infected and KSHV-infected cells. Addressing putative mechanisms, we could show that these proteins could also inhibit the transactivation of the promoters of apoptotic mediators of p53 such as BAX and PIG3. Altogether, we demonstrate for the first time that structural proteins of KSHV can counteract p53-induced apoptosis. These proteins are expressed in the late lytic phase of the viral life cycle and are incorporated into the KSHV virion. Accordingly, these genes may inhibit cell death in the productive and in the early entrance phase of KSHV infection.

Catrina Ene AM, Borze I, Guled M, et al.
MicroRNA expression profiles in Kaposi's sarcoma.
Pathol Oncol Res. 2014; 20(1):153-9 [PubMed] Related Publications
Kaposi's sarcoma (KS) is a mesenchymal tumor, caused by Human herpesvirus 8 (HHV8) with molecular and cytogenetic changes poorly understood. To gain further insight on the underlying molecular changes in KS, we performed microRNA (miRNA) microarray analysis of 17 Kaposi's sarcoma specimens. Three normal skin specimens were used as controls. The most significant differentially expressed miRNA were confirmed by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We detected in KS versus normal skin 185 differentially expressed miRNAs, 76 were upregulated and 109 were downregulated. The most significantly downregulated miRNAs were miR-99a, miR-200 family, miR-199b-5p, miR-100 and miR-335, whereas kshv-miR-K12-4-3p, kshv-miR-K12-1, kshv-miR-K12-2, kshv-miR-K12-4-5p and kshv-miR-K12-8 were significantly upregulated. High expression levels of kshv-miR-K12-1 (p = 0.004) and kshv-miR-K12-4-3p (p = 0.001) was confirmed by RT-PCR. The predicted target genes for differentially expressed miRNAs included genes which are involved in a variety of cellular processes such as angiogenesis (i.e. THBS1) and apoptosis (i.e. CASP3, MCL1), suggesting a role for these miRNAs in Kaposi's sarcoma pathogenesis.

Byun M, Ma CS, Akçay A, et al.
Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood.
J Exp Med. 2013; 210(9):1743-59 [PubMed] Free Access to Full Article Related Publications
Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)-induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4(+) T cells in the peripheral blood, consistent with impaired CD4(+) T cell responses to recall antigens in vitro. The proportion of effector memory CD8(+) T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4(+) T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

Feller K, Yang S, Tung N, et al.
c-myc in Kaposi's sarcoma: analyses by fluorescent in situ hybridization and immunohistochemistry.
J Eur Acad Dermatol Venereol. 2014; 28(1):120-4 [PubMed] Related Publications
BACKGROUND: The c-myc proto-oncogene plays a central role in the regulation of cellular transcription, differentiation, and apoptosis, and has been shown to be deregulated in many types of human cancer. Recent findings have demonstrated its amplification in select vascular neoplasms, such as secondary angiosarcomas, suggesting a role in angiogenesis as well. In vitro studies have shown that the c-Myc protein is an important regulatory molecule of spindle cell proliferation and migration in Kaposi's sarcoma (KS).
OBJECTIVES: In light of these findings, our primary aim was to ascertain whether c-myc, by promoting proliferation and angiogenesis, is an essential co-factor in the aetiopathogenesis of KS. We also attempted to determine a correlation between immunohistochemical expression of the c-Myc protein and c-myc gene copy amplification using fluorescent in situ hybridization (FISH).
METHODS: Samples analyzed included archival tissue of KS (n = 24). PCR for detection of Kaposi's sarcoma-associated herpesvirus DNA was performed on all samples of KS. For FISH analyses, a dual-labelled technique was employed and probes for the c-myc gene and chromosome 8 were used. The monoclonal anti-c-myc antibody, 9E10, was used for immunohistochemical analyses.
RESULTS: While FISH analyses revealed no amplification of c-myc in any of the cases of KS, immunohistochemical analyses revealed positive staining for c-Myc in 13/24 cases (54%).
CONCLUSIONS: Amplification of the c-myc gene was not witnessed in this preliminary study of 24 cases and thus cannot be correlated with the expression of the c-Myc protein.

He M, Zhang W, Bakken T, et al.
Cancer angiogenesis induced by Kaposi sarcoma-associated herpesvirus is mediated by EZH2.
Cancer Res. 2012; 72(14):3582-92 [PubMed] Free Access to Full Article Related Publications
EZH2 is a component of the epigenetic regulator PRC2 that suppresses gene expression. Elevated expression of EZH2 is common in human cancers and is associated with tumor progression and poor prognosis. In this study, we show that EZH2 elevation is associated with epigenetic modifications of Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus that promotes the development of Kaposi sarcoma and other malignancies that occur in patients with chronic HIV infections. KSHV induction of EZH2 expression was essential for KSHV-induced angiogenesis. High expression of EZH2 was observed in Kaposi sarcoma tumors. In cell culture, latent KSHV infection upregulated the expression of EZH2 in human endothelial cells through the expression of vFLIP and LANA, two KSHV-latent genes that activate the NF-κB pathway. KSHV-mediated upregulation of EZH2 was required for the induction of Ephrin-B2, an essential proangiogenic factor that drives endothelial cell tubule formation. Taken together, our findings indicate that KSHV regulates the host epigenetic modifier EZH2 to promote angiogenesis.

Lu F, Tsai K, Chen HS, et al.
Identification of host-chromosome binding sites and candidate gene targets for Kaposi's sarcoma-associated herpesvirus LANA.
J Virol. 2012; 86(10):5752-62 [PubMed] Free Access to Full Article Related Publications
LANA is essential for tethering the Kaposi's sarcoma-associated herpesvirus (KSHV) genome to metaphase chromosomes and for modulating host-cell gene expression, but the binding sites in the host-chromosome remain unknown. Here, we use LANA-specific chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) to identify LANA binding sites in the viral and host-cell genomes of a latently infected pleural effusion lymphoma cell line BCBL1. LANA bound with high occupancy to the KSHV genome terminal repeats (TR) and to a few minor binding sites in the KSHV genome, including the LANA promoter region. We identified 256 putative LANA binding site peaks with P < 0.01 and overlap in two independent ChIP-Seq experiments. We validated several of the high-occupancy binding sites by conventional ChIP assays and quantitative PCR. Candidate cellular LANA binding motifs were identified and assayed for binding to purified recombinant LANA protein in vitro but bound with low affinity compared to the viral TR binding site. More than half of the LANA binding sites (170/256) could be mapped to within 2.5 kb of a cellular gene transcript. Pathways and Gene Ontogeny (GO) analysis revealed that LANA binds to genes within the p53 and tumor necrosis factor (TNF) regulatory network. Further analysis revealed partial overlap of LANA and STAT1 binding sites in several gamma interferon (IFN-γ)-regulated genes. We show that ectopic expression of LANA can downmodulate IFN-γ-mediated activation of a subset of genes, including the TAP1 peptide transporter and proteasome subunit beta type 9 (PSMB9), both of which are required for class I antigen presentation. Our data provide a potential mechanism through which LANA may regulate several host cell pathways by direct binding to gene regulatory elements.

Gregory SM, Wang L, West JA, et al.
Latent Kaposi's sarcoma-associated herpesvirus infection of monocytes downregulates expression of adaptive immune response costimulatory receptors and proinflammatory cytokines.
J Virol. 2012; 86(7):3916-23 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) infection is associated with the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. We report the establishment of a monocytic cell line latently infected with KSHV (KSHV-THP-1). We profiled viral and cytokine gene expression in the KSHV-THP-1 cells compared to that in uninfected THP-1 cells and found that several genes involved in the host immune response were downregulated during latent infection, including genes for CD80, CD86, and the cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Thus, KSHV minimizes its immunological signature by suppressing key immune response factors, enabling persistent infection and evasion from host detection.

Speeckaert R, Colebunders B, Boelaert JR, et al.
Association of haptoglobin phenotypes with the development of Kaposi's sarcoma in HIV patients.
Arch Dermatol Res. 2011; 303(10):763-9 [PubMed] Related Publications
Kaposi's sarcoma (KS) is a rare cutaneous tumor caused by human herpes virus-8 (HHV-8) infection that preferentially develops in case of severe immunosuppression, such as in HIV/AIDS disease. Haptoglobin (Hp), a polymorphic multifunctional plasma protein, exerts several immunomodulatory effects and is characterized by a genetic polymorphism leading to three major phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). This study investigated the influence of Hp genetic polymorphism on the development of KS in HIV-positive patients. 661 HIV patients were enrolled in the study with a median age of 35 years and a median follow-up time of 57 months. Hp phenotyping was performed using hemoglobin-supplemented starch gel electrophoresis. In case of low Hp concentration high pressure gel permeation chromatography (HPGPC) was used. The Hp 1-1 phenotype was associated with a significant higher risk of KS compared to the combined group of Hp 2-1 and Hp 2-2 patients (p < 0.0005) which remained significant after adjustment for possible confounding variables (age, gender and AIDS status) (p < 0.001). In contrast, the Hp 2-1 phenotype carried the lowest risk. These findings point to the involvement of Hp phenotypes in the pathogenesis of KS, which may be due to a difference in skin immunosurveillance between the Hp phenotypes.

Wu YH, Hu TF, Chen YC, et al.
The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility.
Blood. 2011; 118(10):2896-905 [PubMed] Related Publications
miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is up-regulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.

Tornesello ML, Buonaguro L, Cristillo M, et al.
MDM2 and CDKN1A gene polymorphisms and risk of Kaposi's sarcoma in African and Caucasian patients.
Biomarkers. 2011; 16(1):42-50 [PubMed] Related Publications
A single-nucleotide polymorphism in the MDM2 promoter (SNP309; rs2279744) causes elevated transcription of this major negative regulator of p53 in several cancer types. We investigated MDM2 SNP309 and CDKN1A (p21/Waf1/Cip1) codon 31 (rs1801270) polymorphisms in 86 cases of cutaneous Kaposi's sarcoma (KS) from African and Caucasian patients, and 210 healthy controls. A significant increase of the MDM2 SNP309 T/G genotype was observed among classic KS cases (odds ratio 2.38, 95% confidence interval 1.0-5.5). Frequencies of CDKN1A codon 31 genotypes were not significantly different between cases and controls. The results suggest that the MDM2 SNP309 G allele may act as a susceptibility gene for the development of classic KS in Caucasian patients.

Byun M, Abhyankar A, Lelarge V, et al.
Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma.
J Exp Med. 2010; 207(11):2307-12 [PubMed] Free Access to Full Article Related Publications
Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca(2+) entry. STIM1 mRNA splicing, protein production, and Ca(2+) influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.

Alcendor D, Knobel S
Identifying dysregulated genes induced by Kaposi's sarcoma-associated herpesvirus (KSHV).
J Vis Exp. 2010; (43) [PubMed] Free Access to Full Article Related Publications
Currently KS is the most predominant HIV/AIDS related malignancy in Southern Africa and hence the world. It is characterized as an angioproliferative tumor of vascular endothelial cells and produces rare B cell lymphoproliferative diseases in the form of pleural effusion lymphomas (PEL) and some forms of multicentric Castleman's disease. Only 1-5% of cells in KS lesions actively support lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent associated with KS, and it is clear that cellular factors must interact with viral factors in the process of oncogenesis and tumor progression. Identifying novel host-factor determinants which contribute to KS pathology is essential for developing prognostic markers for tumor progression and metastasis as well as for developing novel therapeutics for the treatment of KS. The accompanying video details the methods we use to identify host cell gene expression programs altered in dermal microvascular endothelial cells (DMVEC) after KSHV infection and in KS tumor tissue. Once dysregulated genes are identified by microarray analysis, changes in protein expression are confirmed by immunoblot and dual labeled immunofluorescence. Changes in transcriptional expression of dysregulated genes are confirmed in vitro by quantitative real-time polymerase chain reaction (qRT-PCR). Validation of in vitro findings using archival KS tumor tissue is also performed by dual labeled immunochemistry and tissue microarrays. Our approach to identifying dysregulated genes in the KS tumor tissue microenvironment will allow the development of in vitro and subsequently in vivo model systems for discovery and evaluation of potential novel therapeutic for the treatment of KS.

Dyson OF, Traylen CM, Akula SM
Cell membrane-bound Kaposi's sarcoma-associated herpesvirus-encoded glycoprotein B promotes virus latency by regulating expression of cellular Egr-1.
J Biol Chem. 2010; 285(48):37491-502 [PubMed] Free Access to Full Article Related Publications
One of the important questions in the field of virus research is about the balance between latent and lytic cycles of replication. Kaposi's sarcoma-associated herpesvirus (KSHV) remains predominantly in a latent state, with only 1-3% of cells supporting a lytic replication at any time. KSHV glycoprotein B (gB) is expressed not only on the virus envelope but also on the surfaces of the few cells supporting lytic replication. Using co-culture experiments, we determined that expression of KSHV gB on as few as 1-2% of human dermal microvascular endothelial cells resulted in a 10-fold inhibition of expression of ORF50, a viral gene critical for the onset of lytic replication. Also, we demonstrate that such a profound inhibitory effect of gB on the lytic cycle of virus replication is by repressing the ability of Egr-1 (early growth response-1) to bind and activate the ORF50 promoter. In general, virus-encoded late stage structural proteins, such as gB, are said to play major roles in virus entry and egress. The present report provides initial evidence supporting a role for membrane-associated gB expressed in a minimal number of cells to promote virus latency. These findings may have ramifications leading to a better understanding of the role of virus-encoded structural proteins not only in KSHV-related diseases but also in other viruses causing latent infections.

Sahin G, Palanduz A, Aydogan G, et al.
Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds.
Pediatrics. 2010; 125(3):e704-8 [PubMed] Free Access to Full Article Related Publications
Infection by human herpesvirus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases having been reported since 1960. We recently reported 2 children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this article, we describe 3 unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at 2 years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly, and the patient died within 3 months despite treatment with vincristine. The other 2 children developed a milder form of KS at the age of 9 years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at the age of 14, 2 years after treatment. The second girl is currently stabilized with etoposide, which was begun 4 months ago. None of the 3 children had any relevant familial history or other clinical features. The occurrence of classic KS in 3 unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children.

Punj V, Matta H, Schamus S, et al.
Kaposi's sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a.
Oncogene. 2010; 29(12):1835-44 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) K13 is a potent activator of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that infection with KHSV and ectopic expression of K13, but not its NF-kappaB-defective mutant, suppressed the expression of CXCR4. Suppression of CXCR4 by KSHV and K13 was associated with upregulated expression of miR-146a, a microRNA that is known to bind to the 3'-untranslated region of CXCR4 mRNA. Reporter studies identified two NF-kappaB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-kappaB-defective mutant or other vFLIPs, strongly stimulated the miR-146a promoter activity, which could be blocked by specific genetic and pharmacological inhibitors of the NF-kappaB pathway. Finally, expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by an increased expression of miR-146a. Our results show that K13-induced NF-kappaB activity suppresses CXCR4 through upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting premature release of KSHV-infected endothelial progenitors into the circulation.

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