Kaposi Sarcoma


Literature Analysis

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

  • T-Lymphocytes, Cytotoxic
  • Cancer DNA
  • Endothelial Cells
  • Polymorphism
  • Genes, Viral
  • HLA-DQB1
  • Gene Expression Regulation
  • Acquired Immunodeficiency Syndrome
  • Herpesvirus 8, Human
  • Interleukin-6
  • IL12A
  • Genetic Predisposition
  • Simplexvirus
  • Molecular Sequence Data
  • HIV-1
  • CD40
  • Up-Regulation
  • Skin Cancer
  • Promoter Regions
  • Kaposi Sarcoma
  • Mutation
  • IL4
  • AIDS-Related Opportunistic Infections
  • microRNA mir-1297
  • Cancer Gene Expression Regulation
  • Base Sequence
  • Messenger RNA
  • MART1
  • Risk Factors
  • Amino Acid Sequence
  • Gene Expression Regulation, Viral
  • FGF3
  • HIV Infections
  • Gene Expression Profiling
  • Herpesviridae Infections
  • Oncogenes
  • Viral RNA
  • Polymerase Chain Reaction
  • MicroRNAs
  • Cell Line
  • Immunohistochemistry
  • DNA, Viral
  • Soft Tissue Cancers
  • Transfection
  • Genotype
  • Case-Control Studies
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (18)

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 20q13.12 p50, Bp50, CDW40, TNFRSF5 -CD40 and Kaposi's Sarcoma
IKBKB 8p11.21 IKK2, IKKB, IMD15, NFKBIKB, IKK-beta -IKBKB and Kaposi 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
PDGFRB 5q32 IMF1, KOGS, IBGC4, JTK12, PDGFR, PENTT, CD140B, PDGFR1, PDGFR-1 -PDGFRB and Kaposi Sarcoma
IL4 5q31.1 BSF1, IL-4, BCGF1, BSF-1, BCGF-1 -IL4 and Kaposi Sarcoma
HLA-DQA1 6p21.32 DQ-A1, CELIAC1, HLA-DQA -HLA-DQA1 and Kaposi Sarcoma
IL13 5q31.1 P600, IL-13 -IL13 and Kaposi Sarcoma
MLANA 9p24.1 MART1, MART-1 -MLANA and Kaposi Sarcoma
HLA-DRA 6p21.32 HLA-DRA1 -HLA-DRA and Kaposi Sarcoma
IL1B 2q14 IL-1, IL1F2, IL1-BETA -IL1B and Kaposi Sarcoma
IL12A 3q25.33 P35, CLMF, NFSK, NKSF1, IL-12A -IL12A 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
HLA-DQB1 6p21.32 IDDM1, CELIAC1, HLA-DQB -HLA-DQB1 and Kaposi Sarcoma
MIR1297 13q14.3 MIRN1297, mir-1297, hsa-mir-1297 -MIRN1297 microRNA, human and Kaposi Sarcoma
FCGR3A 1q23.3 CD16, FCG3, CD16A, FCGR3, IGFR3, IMD20, FCR-10, FCRIII, FCGRIII, FCRIIIA -FCGR3A and Kaposi Sarcoma
APOE 19q13.32 AD2, LPG, APO-E, ApoE4, LDLCQ5 -APOE 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

Gong HB, Wu XJ, Pu XM, Kang XJ
Bioinformatics analysis of key biomarkers and pathways in KSHV infected endothelial cells.
Medicine (Baltimore). 2019; 98(27):e16277 [PubMed] Free Access to Full Article Related Publications
Kaposi sarcoma (KS) is an endothelial tumor etiologically related to Kaposi sarcoma herpesvirus (KSHV) infection. The aim of our study was to screen out candidate genes of KSHV infected endothelial cells and to elucidate the underlying molecular mechanisms by bioinformatics methods. Microarray datasets GSE16354 and GSE22522 were downloaded from Gene Expression Omnibus (GEO) database. the differentially expressed genes (DEGs) between endothelial cells and KSHV infected endothelial cells were identified. And then, functional enrichment analyses of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed. After that, Search Tool for the Retrieval of Interacting Genes (STRING) was used to investigate the potential protein-protein interaction (PPI) network between DEGs, Cytoscape software was used to visualize the interaction network of DEGs and to screen out the hub genes. A total of 113 DEGs and 11 hub genes were identified from the 2 datasets. GO enrichment analysis revealed that most of the DEGs were enrichen in regulation of cell proliferation, extracellular region part and sequence-specific DNA binding; KEGG pathway enrichments analysis displayed that DEGs were mostly enrichen in cell cycle, Jak-STAT signaling pathway, pathways in cancer, and Insulin signaling pathway. In conclusion, the present study identified a host of DEGs and hub genes in KSHV infected endothelial cells which may serve as potential key biomarkers and therapeutic targets, helping us to have a better understanding of the molecular mechanism of KS.

Rose TM, Bruce AG, Barcy S, et al.
Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter.
PLoS Pathog. 2018; 14(12):e1007441 [PubMed] Free Access to Full Article Related Publications
KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV transcriptome. Phylogenetic analysis of ORF75 sequences from 23 tumors revealed 6 distinct genetic clusters with KSHV strains exhibiting M, N or P alleles. RNA reads mapping to specific unique coding sequence (UCDS) features were quantitated using a gene feature file previously developed to globally analyze and quantitate KSHV transcription in infected endothelial cells. A pattern of high level expression was detected in the KSHV latency region that was common to all KS tumors. The clear majority of transcription was derived from the downstream latency transcript promoter P3(LTd) flanking ORF72, with little evidence of transcription from the P1(LTc) latency promoter, which is constitutive in KSHV-infected lymphomas and tissue-culture cells. RNAseq data provided evidence of alternate P3(LTd) transcript editing, splicing and termination resulting in multiple gene products, with 90% of the P3(LTd) transcripts spliced to release the intronic source of the microRNAs K1-9 and 11. The spliced transcripts encode a regulatory uORF upstream of Kaposin A with alterations in intervening repeat sequences yielding novel or deleted Kaposin B/C-like sequences. Hierarchical clustering and PCA analysis of KSHV transcripts revealed three clusters of tumors with different latent and lytic gene expression profiles. Paradoxically, tumors with a latent phenotype had high levels of total KSHV transcription, while tumors with a lytic phenotype had low levels of total KSHV transcription. Morphologically distinct KS tumors from the same individual showed similar KSHV gene expression profiles suggesting that the tumor microenvironment and host response play important roles in the activation level of KSHV within the infected tumor cells.

Tagawa T, Gao S, Koparde VN, et al.
Discovery of Kaposi's sarcoma herpesvirus-encoded circular RNAs and a human antiviral circular RNA.
Proc Natl Acad Sci U S A. 2018; 115(50):12805-12810 [PubMed] Free Access to Full Article Related Publications
Noncoding RNAs have substantial effects in host-virus interactions. Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs which can decoy other RNAs or RNA-binding proteins to inhibit their functions. The role of circRNAs is largely unknown in the context of Kaposi's sarcoma herpesvirus (KSHV). We hypothesized that circRNAs influence viral infection by inhibiting host and/or viral factors. Transcriptome analysis of KSHV-infected primary endothelial cells and a B cell line identified human circRNAs that are differentially regulated upon infection. We confirmed the expression changes with divergent PCR primers and RNase R treatment of specific circRNAs. Ectopic expression of hsa_circ_0001400, a circRNA induced by infection, suppressed expression of key viral latent gene

Lu G, Wu X, Zhao Z, et al.
MicroRNA-126 regulates the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in SLK cells in vitro and the expression of its pathway members in Kaposi's sarcoma tissue.
Medicine (Baltimore). 2018; 97(35):e11855 [PubMed] Free Access to Full Article Related Publications
In vitro, microRNA-126 (miR-126) inhibits SLK cell proliferation, inhibits the cell cycle, induces cell apoptosis, and reduces cell invasiveness. Double luciferase assays have shown that phosphatidylinositol-3 kinase (PI3K) is the miR-126 target in SLK cells. We aimed to investigate the influence of miR-126 on the phosphate and tension homology deleted on chromosome ten (PTEN)/PI3K/protein kinase B (AKT) pathway members in SLK cells and to determine the expression of these pathway members in Kaposi's sarcoma (KS). The mimic and inhibitor of miR-126 were transfected into SLK cells and PTEN and AKT1 expression was assayed in SLK cells by real-time quantitative PCR and western blotting. PTEN, AKT1, phosphorylated (P)-PTEN, and phosphorylated (P)-AKT expression in KS and paraneoplastic skin were assayed by immunohistochemistry. AKT1 expression was downregulated in SLK cells that overexpressed miR-126, while there was no significant difference in PTEN expression between SLK cells overexpressing miR-126 and those in which its expression was knocked down. PTEN and AKT1 were expressed in KS and paraneoplastic skin but P-AKT was not. Interestingly, P-PTEN was not expressed in paraneoplastic skin but it was expressed in 90% of KS biopsies (P < .05). P-PTEN expression was also significantly higher in visceral than in cutaneous KS (P = .01) and was higher in indoor than in outdoor workers (P = .018). In vitro, miR-126 negatively regulated AKT1 expression but no regulation of PTEN expression was evident. Results indicated that in KS, PTEN is activated and may therefore be a potential therapeutic target for KS. In addition, these results also indicate that sunlight may not be the cause of KS.

Strahan R, Dabral P, Dingman K, et al.
Kaposi's Sarcoma-Associated Herpesvirus Deregulates Host Cellular Replication during Lytic Reactivation by Disrupting the MCM Complex through ORF59.
J Virol. 2018; 92(22) [PubMed] Free Access to Full Article Related Publications
Minichromosome maintenance proteins (MCMs) play an important role in DNA replication by binding to the origins as helicase and recruiting polymerases for DNA synthesis. During the S phase, MCM complex is loaded to limit DNA replication once per cell cycle. We identified MCMs as ORF59 binding partners in our protein pulldown assays, which led us to hypothesize that this interaction influences DNA replication. ORF59's interactions with MCMs were confirmed in both endogenous and overexpression systems, which showed its association with MCM3, MCM4, MCM5, and MCM6. Interestingly, MCM6 interacted with both the N- and C-terminal domains of ORF59, and its depletion in BCBL-1 and BC3 cells led to an increase in viral genome copies, viral late gene transcripts, and virion production compared to the control cells following reactivation. MCMs perform their function by loading onto the replication competent DNA, and one means of regulating chromatin loading/unloading, in addition to enzymatic activity of the MCM complex, is by posttranslational modifications, including phosphorylation of these factors. Interestingly, a hypophosphorylated form of MCM3, which is associated with reduced loading onto the chromatin, was detected during lytic reactivation and correlated with its inability to associate with histones in reactivated cells. Additionally, chromatin immunoprecipitation showed lower levels of MCM3 and MCM4 association at cellular origins of replication and decreased levels of cellular DNA synthesis in cells undergoing reactivation. Taken together, these findings suggest a mechanism in which KSHV ORF59 disrupts the assembly and functions of MCM complex to stall cellular DNA replication and promote viral replication.

Hussein HAM, Okafor IB, Walker LR, et al.
Cellular and viral oncogenes: the key to unlocking unknowns of Kaposi's sarcoma-associated herpesvirus pathogenesis.
Arch Virol. 2018; 163(10):2633-2643 [PubMed] Related Publications
Oncogenic viruses carry an extensive arsenal of oncogenes for hijacking cellular pathways. Notably, variations in oncogenes among tumor-producing viruses give rise to different mechanisms for cellular transformation. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus able to infect and transform a variety of cell types. The oncogenicity of KSHV disseminates from the virus' ability to induce and encode a wide variety of both cellular and viral oncogenes. Such an array of cellular and viral oncogenes enables KSHV to induce the malignant phenotype of a KSHV-associated cancer. Evolutionarily, KSHV has acquired many oncogenic homologues capable of inducing cell proliferation, cell differentiation, cell survival, and immune evasion. Integration between inducing and encoding oncogenes plays a vital role in KSHV pathogenicity. KSHV is alleged to harbor the highest number of potential oncogenes by which a virus promotes cellular transformation and malignancy. Many KSHV inducing/encoding oncogenes are mainly expressed during the latent phase of KSHV infection, a period required for virus establishment of malignant cellular transformation. Elucidation of the exact mechanism(s) by which oncogenes promote KSHV pathogenicity would not only give rise to potential novel therapeutic targets/drugs but would also add to our understanding of cancer biology. The scope of this review is to examine the roles of the most important cellular and viral oncogenes involved in KSHV pathogenicity.

Dai L, Del Valle L, Miley W, et al.
Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi's sarcoma development.
Oncogene. 2018; 37(33):4534-4545 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers such as Kaposi's sarcoma (KS), which represents the most common AIDS-associated malignancy that lacks effective treatment options. Despite its clear role in AIDS malignancies, the fact that only a small set of KSHV-infected patients will eventually develop these tumors implies that additional co-factors are required for the development of KSHV-related cancers. In the current study, we demonstrate for the first time that KSHV de novo infection or viral latent proteins are able to transactivate human endogenous retrovirus K (HERV-K) through a variety of cellular signaling pathways and transcriptional factors. Moreover, we found that HERV-K transactivation, particularly activation of its encoded oncogenic NP9 protein, plays an important role in KSHV pathogenesis and tumorigenesis in vitro and in vivo. Our data provide innovative insights into the mechanisms of HERV-K transactivation contributing to viral oncogenesis, which may represent a promising target for KS treatment.

Gay LA, Sethuraman S, Thomas M, et al.
Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells.
J Virol. 2018; 92(8) [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma (KS) tumors are derived from endothelial cells and express Kaposi's sarcoma-associated herpesvirus (KSHV) microRNAs (miRNAs). Although miRNA targets have been identified in B cell lymphoma-derived cells and epithelial cells, little has been done to characterize the KSHV miRNA targetome in endothelial cells. A recent innovation in the identification of miRNA targetomes, cross-linking, ligation, and sequencing of hybrids (CLASH), unambiguously identifies miRNAs and their targets by ligating the two species while both species are still bound within the RNA-induced silencing complex (RISC). We developed a streamlined quick CLASH (qCLASH) protocol that requires a lower cell input than the original method and therefore has the potential to be used on patient biopsy samples. Additionally, we developed a fast-growing, KSHV-negative endothelial cell line derived from telomerase-immortalized vein endothelial long-term culture (TIVE-LTC) cells. qCLASH was performed on uninfected cells and cells infected with either wild-type KSHV or a mutant virus lacking miR-K12-11/11*. More than 1,400 cellular targets of KSHV miRNAs were identified. Many of the targets identified by qCLASH lacked a canonical seed sequence match. Additionally, most target regions in mRNAs originated from the coding DNA sequence (CDS) rather than the 3' untranslated region (UTR). This set of genes includes some that were previously identified in B cells and some new genes that warrant further study. Pathway analysis of endothelial cell targets showed enrichment in cell cycle control, apoptosis, and glycolysis pathways, among others. Characterization of these new targets and the functional consequences of their repression will be important in furthering our understanding of the role of KSHV miRNAs in oncogenesis.

Tso FY, Kossenkov AV, Lidenge SJ, et al.
RNA-Seq of Kaposi's sarcoma reveals alterations in glucose and lipid metabolism.
PLoS Pathog. 2018; 14(1):e1006844 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). It is endemic in a number of sub-Saharan African countries with infection rate of >50%. The high prevalence of HIV-1 coupled with late presentation of advanced cancer staging make KS the leading cancer in the region with poor prognosis and high mortality. Disease markers and cellular functions associated with KS tumorigenesis remain ill-defined. Several studies have attempted to investigate changes of the gene profile with in vitro infection of monoculture models, which are not likely to reflect the cellular complexity of the in vivo lesion environment. Our approach is to characterize and compare the gene expression profile in KS lesions versus non-cancer tissues from the same individual. Such comparisons could identify pathways critical for KS formation and maintenance. This is the first study that utilized high throughput RNA-seq to characterize the viral and cellular transcriptome in tumor and non-cancer biopsies of African epidemic KS patients. These patients were treated anti-retroviral therapy with undetectable HIV-1 plasma viral load. We found remarkable variability in the viral transcriptome among these patients, with viral latency and immune modulation genes most abundantly expressed. The presence of KSHV also significantly affected the cellular transcriptome profile. Specifically, genes involved in lipid and glucose metabolism disorder pathways were substantially affected. Moreover, infiltration of immune cells into the tumor did not prevent KS formation, suggesting some functional deficits of these cells. Lastly, we found only minimal overlaps between our in vivo cellular transcriptome dataset with those from in vitro studies, reflecting the limitation of in vitro models in representing tumor lesions. These findings could lead to the identification of diagnostic and therapeutic markers for KS, and will provide bases for further mechanistic studies on the functions of both viral and cellular genes that are involved.

Qin J, Lu C
Infection of KSHV and Interaction with HIV: The Bad Romance.
Adv Exp Med Biol. 2017; 1018:237-251 [PubMed] Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV), namely, human herpesvirus 8 (HHV-8), is considered as the pathogen of Kaposi's sarcoma (KS), the most frequent cancer in untreated HIV-infected individuals. Patients infected with HIV have a much higher possibility developing KS than average individual. Researchers have found that HIV, which functions as a cofactor of KS, contributes a lot to the development of KS. In this article, we will give a brief introduction of KS and KSHV and how the interaction between KSHV and HIV contributes to the development of KS. Also we will take a glance at the development of treatment in KS, especially AIDS-KS.

Li S, Bai L, Dong J, et al.
Kaposi's Sarcoma-Associated Herpesvirus: Epidemiology and Molecular Biology.
Adv Exp Med Biol. 2017; 1018:91-127 [PubMed] Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8), is a member of the lymphotropic gammaherpesvirus subfamily and a human oncogenic virus. Since its discovery in AIDS-associated KS tissues by Drs. Yuan Chang and Patrick Moore, much progress has been made in the past two decades. There are four types of KS including classic KS, endemic KS, immunosuppressive therapy-related KS, and AIDS-associated KS. In addition to KS, KSHV is also involved in the development of primary effusion lymphoma (PEL) and certain types of multicentric Castleman's disease. KSHV manipulates numerous viral proteins to promote the progression of angiogenesis and tumorigenesis. In this chapter, we review the epidemiology and molecular biology of KSHV and the mechanisms underlying KSHV-induced diseases.

Gruffaz M, Vasan K, Tan B, et al.
TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway.
Cancer Res. 2017; 77(24):7094-7108 [PubMed] Free Access to Full Article Related Publications
Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi sarcoma is caused by infection of Kaposi sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here, we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human Kaposi sarcoma lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral miRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells, resulting in chronic induction of IL6, IL1β, and IL18. Accordingly, IL6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop Kaposi sarcoma.

Sethuraman S, Gay LA, Jain V, et al.
microRNA dependent and independent deregulation of long non-coding RNAs by an oncogenic herpesvirus.
PLoS Pathog. 2017; 13(7):e1006508 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma (KS) is a highly prevalent cancer in AIDS patients, especially in sub-Saharan Africa. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of KS and other cancers like Primary Effusion Lymphoma (PEL). In KS and PEL, all tumors harbor latent KSHV episomes and express latency-associated viral proteins and microRNAs (miRNAs). The exact molecular mechanisms by which latent KSHV drives tumorigenesis are not completely understood. Recent developments have highlighted the importance of aberrant long non-coding RNA (lncRNA) expression in cancer. Deregulation of lncRNAs by miRNAs is a newly described phenomenon. We hypothesized that KSHV-encoded miRNAs deregulate human lncRNAs to drive tumorigenesis. We performed lncRNA expression profiling of endothelial cells infected with wt and miRNA-deleted KSHV and identified 126 lncRNAs as putative viral miRNA targets. Here we show that KSHV deregulates host lncRNAs in both a miRNA-dependent fashion by direct interaction and in a miRNA-independent fashion through latency-associated proteins. Several lncRNAs that were previously implicated in cancer, including MEG3, ANRIL and UCA1, are deregulated by KSHV. Our results also demonstrate that KSHV-mediated UCA1 deregulation contributes to increased proliferation and migration of endothelial cells.

Wang Y, Lin Y, Guo Y, et al.
Functional dissection of human targets for KSHV-encoded miRNAs using network analysis.
Sci Rep. 2017; 7(1):3159 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease, etc. In this study, we firstly systematically constructed the KSHV-encoded miRNA-regulated co-expressed protein-protein interaction network (CePPIN), which display the biological knowledge regarding the mechanism of miRNA-regulated KSHV pathogenesis. Then, we investigated the topological parameters for the proteins in CePPIN, especially for those miRNA targets and we found that cellular target genes of KSHV-encoded miRNAs tend to be hubs and bottlenecks in the network. Then the GO and KEGG pathway analysis suggests that miRNA targets are involved in various cellular processes mostly related to immune regulate and cell cycle. Enrichment analysis was also performed to identify the six important functional modules which are proven to be highly related to KSHV pathogenesis. Finally, difference analysis of common targets and specific targets shows that two kinds of targets are different in terms of both topological properties and enriched functions, thus we can extrapolate that the functions of KSHV-encoded miRNAs can be also classified into two generic groups, one can act as functional mimics of some oncogenic human miRNAs which contribute to tumorigenesis and the other can contribute to maintaining viral survival.

Gloghini A, Volpi CC, Gualeni AV, et al.
Multiple viral infections in primary effusion lymphoma: a model of viral cooperation in lymphomagenesis.
Expert Rev Hematol. 2017; 10(6):505-514 [PubMed] Related Publications
INTRODUCTION: Primary effusion lymphoma (PEL) is a rare B-cell lymphoid neoplasm mainly associated with HIV infection, presenting as pleural, peritoneal, and pericardial effusions. A defining property of PEL is its consistent association with Kaposi sarcoma associated herpesvirus (KSHV) infection, and, in most cases, Epstein Barr virus (EBV) co-infection. On these grounds, a review of the literature related to viral cooperation and lymphomagenesis can help to understand the complex interplay between KSHV and EBV in PEL pathogenesis. Areas covered: In this review, the authors highlight clinical, pathologic, genetic and proteomic features of PEL, in the context of viral cooperation in PEL lymphomagenesis. Expert commentary: Tumour cells are characterized by the overexpression of genes that are involved in inflammation and invasion. Coherently, PEL secretomes are enriched in proteins probably responsible for the particular tropism (cell adhesion and migration) of PEL cells. The development of PEL in HIV+ patients is multifactorial and involves a complex interplay among co-infection with oncogenic viruses (EBV and KSHV), inflammatory factors, and environmental conditions.

Ke ZY, Yang SJ
[Role of master transcriptional factor Prox-1 in lymphatic endothelial differentiation of Kaposiform hemangioendothelioma].
Zhonghua Bing Li Xue Za Zhi. 2017; 46(3):176-181 [PubMed] Related Publications

Egashira S, Jinnin M, Harada M, et al.
Exome sequence analysis of Kaposiform hemangioendothelioma: identification of putative driver mutations.
An Bras Dermatol. 2016 Nov-Dec; 91(6):748-753 [PubMed] Free Access to Full Article Related Publications
BACKGROUND:: Kaposiform hemangioendothelioma is a rare, intermediate, malignant tumor. The tumor's etiology remains unknown and there are no specific treatments.
OBJECTIVE:: In this study, we performed exome sequencing using DNA from a Kaposiform hemangioendothelioma patient, and found putative candidates for the responsible mutations.
METHOD:: The genomic DNA for exome sequencing was obtained from the tumor tissue and matched normal tissue from the same individual. Exome sequencing was performed on HiSeq2000 sequencer platform.
RESULTS:: Among oncogenes, germline missense single nucleotide variants were observed in the TP53 and APC genes in both the tumor and normal tissue. As tumor-specific somatic mutations, we identified 81 candidate genes, including 4 nonsense changes, 68 missense changes and 9 insertions/deletions. The mutations in ITGB2, IL-32 and DIDO1 were included in them.
CONCLUSION:: This is a pilot study, and future analysis with more patients is needed to clarify: the detailed pathogenesis of this tumor, the novel diagnostic methods by detecting specific mutations, and the new therapeutic strategies targeting the mutation.

Varmazyar S, Marashi SM, Shoja Z, et al.
MDM2 gene polymorphisms and risk of classic Kaposi's sarcoma among Iranian patients.
Med Microbiol Immunol. 2017; 206(2):157-163 [PubMed] Related Publications
A single-nucleotide polymorphism (SNP) in the promoter region of MDM2 (SNP309T>G, rs2279744) has been shown to increase the expression of the MDM2 protein in various cancer types. However, only one study has analyzed the role of the MDM2 polymorphism in the development of Kaposi's sarcoma (KS). The association of MDM2 SNP309 with classic KS risk was evaluated in 79 Iranian patients with classic KS and 123 healthy controls. The MDM2 SNP309 was genotyped using PCR and restriction fragment length polymorphism methods. No significant correlation was found between the SNP309 polymorphism in MDM2 promoter and classic KS risk. There was no significant correlation between gender and disease stage. However, a significant association was found between SNP309 GG genotype and younger age (≤50 years) (odds ratio 9.5, 95% confidence intervals 1.5-60, p = 0.03). Our findings support no major role for the MDM2 SNP309 in KS development although it might influence the clinical outcome of KS in younger patients.

Viollet C, Davis DA, Tekeste SS, et al.
RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature.
PLoS Pathog. 2017; 13(1):e1006143 [PubMed] Free Access to Full Article Related Publications
Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.

Gao H, Song Y, Liu C, Liang Q
KSHV strategies for host dsDNA sensing machinery.
Virol Sin. 2016; 31(6):466-471 [PubMed] Related Publications
The innate immune system utilizes pattern recognition receptors cyclic GMP-AMP synthase (cGAS) to sense cytosolic double-stranded (ds) DNA and initiate type 1 interferon signaling and autophagy pathway, which collaborate to limit pathogen infections as well as alarm the adaptive immune response. The genomes of herpesviruses are large dsDNA, which represent a major class of pathogen signatures recognized by cellular DNA sensor cGAS. However, to successfully establish the persistent infection, herpesviruses have evolved their viral genes to modulate different aspects of host immune signaling. This review summarizes the evasion strategies of host cGAS DNA sensing pathway by Kaposi's Sarcoma-associated Herpesvirus (KSHV) and their contributions to KSHV life cycles.

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.

Dai L, Bai L, Lin Z, et al.
Transcriptomic analysis of KSHV-infected primary oral fibroblasts: The role of interferon-induced genes in the latency of oncogenic virus.
Oncotarget. 2016; 7(30):47052-47060 [PubMed] Free Access to Full Article Related Publications
The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but the mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found within KS lesions, and KSHV can establish latent infection within human primary fibroblasts in vitro and in vivo, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. In the present study, we used Illumina microarray to determine global gene expression changes in KSHV-infected primary human oral fibroblasts (PDLF and HGF). Among significantly altered candidates, we found that a series of interferon-induced genes were strongly up-regulated in these KSHV-infected oral cells. Interestingly, some of these genes in particular ISG15 and ISG20 are required for maintenance of virus latency through regulation of specific KSHV microRNAs. Our data indicate that oral fibroblasts may represent one important host cellular defense component against viral infection, as well as acting as a reservoir for herpesvirus lifelong infection in the oral cavity.

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.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. Kaposi Sarcoma, Cancer Genetics Web: http://www.cancer-genetics.org/X2004.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 29 August, 2019     Cancer Genetics Web, Established 1999