Upregulation of xCT by KSHV-Encoded microRNAs Facilitates KSHV Dissemination and Persistence in an Environment of Oxidative Stress

Qin, Zhiqiang; Freitas, Eduardo; Sullivan, Roger J.; Mohan, Sarumathi; Bacelieri, Rocky; Branch, Drake; Romano, Margaret; Kearney, Patricia M.; Oates, Jim C.; Plaisance, Karlie; Renne, Rolf; Kaleeba, Johnan A.R.; Parsons, Chris

doi:10.1371/journal.ppat.1000742

Cited by 100 publications

(113 citation statements)

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“…Thus far, miRNA studies have been constrained by sensitivity limits for detection of individual miRNAs and for the discovery of miRNA-target interactions. Targets with functions that seem to befit the biology of B cell development, endothelial cell differentiation, and KSHV (such as BACH1, xCT, MAF, and others) have been individually validated (132)(133)(134). These are by no means the only targets, and it is anticipated that additional targets will be identified in the future.…”

Section: Viral Mirnas Support Viral Infection and Latent Persistencementioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

171

152

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Section: Viral Mirnas Support Viral Infection and Latent Persistencementioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

171

152

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“…In the case of KS, as malignancy it was early reported in HIV-infected patients since the first cases in 1982; oxidative stress is suggested to interact with all multistage process of this coinfection, i.e., initiation, promotion, and progression [17]. How oxidative stress is involved in these various steps is the object of revision and investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Data that support the contribution of oxidative stress in AIDS-KS pathogenesis has also been accrued at the cellular biochemical level [16][17][18][19]. In vitro studies conducted by Ye et al showed that AIDS-KS strains demonstrate enhanced susceptibility to oxidative stress as induced by either physiologically relevant levels of hydrogen peroxide [18] or conducted by Li et al who show activation through a drug capable of undergoing redox cycling (doxorubicin) [19].…”

Section: Multivariate Discriminant Analysis Of Redox and Progressionmentioning

confidence: 99%

“…All forms of KS are characterized by high levels of inflammation which could mediate oxidative stress as a result of host responses to HIV infection and HHV-8. Those events imply that due to their impaired antioxidant scavenging capacities and thiol redox perturbations, AIDS-KS cells are inherently susceptible to the deleterious, tumorigenic consequences of oxidative stimulus [16,17].…”

Section: Multivariate Discriminant Analysis Of Redox and Progressionmentioning

confidence: 99%

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Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

Valle¹,

Duque-Vizcaino²,

Calás-Hechavarria³

et al. 2017

Oxid Antioxid Med Sci

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Objectives: Infection by human immunodeficiency virus (HIV) generates sustained reactive oxygen species production. An increasing number of studies underline the pathogenic impact of high-grade local and systemic oxidative stress in the activation of Herpesvirus 8 producing Kaposi's sarcoma (KS) co-infection in acquired immunodeficiency syndrome (AIDS) patients. This study aimed to determine the redox status in AIDS-KS Cuban individuals and to explore the relation between redox and progression variables. Methods: Blood samples were drawn from 99 individuals divided into three groups (33 each one; age range 30-50 years): AIDS, AIDS-KS, and presumable healthy subjects. Total peroxide, malondialdehyde, and advanced oxidation protein products as damage indexes and antioxidant responses (glutathione, peroxidation potential, superoxide dismutase, and catalase) were determined from the blood samples. Furthermore, hematological and hemochemical indexes, progression indexes (viral load, CD4 + T lymphocyte absolute count), and tumoral progression indexes were assessed. Different statistical analyses were done. Results: Compared to healthy subjects, both groups of AIDS patients had significant differences in global indices of damage and antioxidant status. The comparison between the groups revealed that AIDS-KS group had a significantly higher damage and lower antioxidant status compared to the healthy control and AIDS groups. Multivariate statistical analysis clearly separated groups according progression indexes and redox profile, obtaining two canonical functions. Conclusions: These results corroborate that substantial oxidative stress occurs in AIDS condition and also during KS-HIV co-infection with different molecular extension and interdependence to progression indexes. Redox indexes diagnosis should be considered in early diagnostics, prevention and treatment of KS-HIV coinfection, which would be worthwhile to conduct a more comprehensive study and manage of infection.

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“…In suppressing BACH1, the membranebound subunit of the amino acid transporter xCT increases, thus intracellular glutathione stores remain full providing protection against oxidative stress. Further, xCT is the cell surface receptor for the entry of KSHV (454). The Orf63 of KSHV is homologous to the cellular NLR (nucleotide binding and oligomerization, leucinerich repeat), which activates innate immune reactions in the inflammasome.…”

mentioning

confidence: 99%

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

Sinkovics

2011

Int J Oncol

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Abstract. In some inflammasomes tumor cells are generated. The internal environment of the inflammasome is conducive to the induction of malignant transformation. Epigenetic changes initiate this process. The subverted stromal connective tissue cells act to promote and sustain the process of malignant trans formation. In its early stages, the premalignant cells depend on paracrine circuitries for the reception of growth factors. The ligands are derived from the connective tissue, and the receptors are expressed on the recipient premalignant cells. The initial events are not a direct attack on the protooncogenes, and thus it may be entirely reversible. Epigenetic processes of hypermethylation of the genes at the promoters of tumor suppressor genes (to silence them), and deacetylation of the histones aimed at the promoters of protooncogenes (to activate them) are ongoing. A large number of short RNA sequences (interfering, micro, short hairpin, noncoding RNAs) silence tumor suppressor genes, by neutralizing their mRNAs. In a serial sequence oncogenes undergo amplifications, pointmutations, translocations and fusions. In its earliest stage, the process is reversible by demethylation of the silenced suppressor gene promoters (to reactivate them), or reacetylation of the histones of the oncogene promoters, thus deactivating them. The external administration of histone deacetylase inhibitors usually leads to the restoration of histone acetylation. In time, the uncorrected processes solidify into constitutive and irreversible gene mutations. Some of the pathogens inducing inflammations with consquential malignant transformation contain oncogenic gene sequences (papilloma viruses, EpsteinBarr virus, Kaposi's sarcomaassociated herpesvirus, hepatitis B and C viruses, Merkel cell polyoma virus, Helicobacter pylori, enterotoxigenic Bacteroides fragilis). These induced malignancies may be multifocal. Other pathogens are devoid of any known oncogenic genomic sequences (mycoplasma vavcarcinogenesis, chlamydia MALTlymphoma genesis). In these cases the host's inflammatory reactions induce the malignant transformation in serial sequences of gene alterations initiated by hypoxia and reactive oxygen and nitrogen species generation. Carcinogenic intrinsic inflammatory processes endogenously initiated without a pathogen are recognized. Chronic inflammatory processes signal the RNA/DNA complex. In response, the DNA may revert into its ancient primordial 'immortal' format, which the clinics recognize as 'oncogenesis'. The DNA remains the ultimate master of bioengineering in order to sustain life. A discussion on the most versatile and resistant primordial RNA/ DNA complex and the pre, proto, and unicellular world in which they coexisted is included. Contents1. Pathogens without oncogenic genomic sequences activating cellular oncogenes 2. The inflammasome 3. Tumor cell colonies generated in the inflammasomes 4. Pathogens with potentially oncogenic genomic sequences 5. Mechanisms of inflammatory carcinogenesis Pathogens without oncogenic...

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Upregulation of xCT by KSHV-Encoded microRNAs Facilitates KSHV Dissemination and Persistence in an Environment of Oxidative Stress

Cited by 100 publications

References 69 publications

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

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