The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA

Wan, Li; Yan, Qin; Ding, Xiangya; Shen, Chenyou; Mei, Hu; Zhu, Ying; Qin, Di; Lü, Hongmei; Krueger, Brian J.; Renne, Rolf; Gao, Shou‐Jiang; Liu, Chun

doi:10.1371/journal.ppat.1005605

Cited by 44 publications

(49 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This proper regulation is likely achieved through a mixture of positive and negative regulators. A recent study reported an indirect activation of STAT3 by KSHV-encoded miRNAs (including miR-K6)41. Previously, we tested sixteen KSHV miRNAs in primary endothelial cells and no miRNAs increased STAT3 protein levels15.…”

Section: Discussionmentioning

confidence: 90%

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

Ramalingam

Ziegelbauer

2017

Sci Rep

View full text Add to dashboard Cite

Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs during latency that are processed to yield ~25 mature microRNAs (miRNAs). We were interested in identifying cellular networks that were targeted by KSHV-miRNAs and employed network building strategies using validated KSHV miRNA targets. Here, we report the identification of a gene network centering on the transcription factor- signal transducer and activator of transcription 3 (STAT3) that is targeted by KSHV miRNAs. KSHV miRNAs suppressed STAT3 and STAT5 activation and inhibited STAT3-dependent reporter activation upon IL6-treatment. KSHV miRNAs also repressed the induction of antiviral interferon-stimulated genes upon IFNα- treatment. Finally, we observed increased lytic reactivation of KSHV from latently infected cells upon STAT3 repression with siRNAs or a small molecule inhibitor. Our data suggest that treatment of infected cells with a STAT3 inhibitor and a viral replication inhibitor, ganciclovir, represents a possible strategy to eliminate latently infected cells without increasing virion production. Together, we show that KSHV miRNAs suppress a network of targets associated with STAT3, deregulate cytokine-mediated gene activation, suppress an interferon response, and influence the transition into the lytic phase of viral replication.

show abstract

Section: Discussionmentioning

confidence: 90%

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

Ramalingam

Ziegelbauer

2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…LANA physically interacts with STAT3 and enhances STAT3 transcriptional activity (44) while vGPCR constitutively activates STAT3 independent of IL-6R (45). Kaposin B and miR-K6–3p activates STAT3 by inducing its phosphorylation and targeting negative regulator SH3BGR, respectively (46, 47). vIL-6 also activates the STAT3 pathway through the gp130 subunit (48).…”

Section: Discussionmentioning

confidence: 99%

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

et al. 2017

Self Cite

View full text Add to dashboard Cite

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’s sarcoma (KS) is caused by infection of Kaposi’s 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 KS 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 microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 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 KS.

show abstract

“…BAC16‐based mutagenesis has also been employed to several studies of KSHV‐encoded 25 mature miRNAs derived from 12 pre‐miRNAs in viral latency and the development of KSHV‐related malignancies By producing BAC16 miR‐K3 mutant viruses, we previously demonstrated that deletion of miR‐K3 from the KSHV genome attenuated KSHV‐induced cell migration and invasion, and also disrupted KSHV latency and impaired angiogenesis . Similarly, with the deletion of miR‐K6 relying on BAC16, we further found that absence of miR‐K6 disturbed cell invasion, migration, and angiogenesis induced by KSHV…”

Section: Discussionmentioning

confidence: 99%

Generation of a KSHV K13 deletion mutant for vFLIP function study

Wang

Guo

Wan

et al. 2018

Journal of Medical Virology

Self Cite

View full text Add to dashboard Cite

Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral Fas-associated death domain-like IL-1-converting enzyme inhibitory protein (vFLIP) is one of the latently expressed genes and plays a key role in cell survival and maintenance of latent infection by activating the NF-κB pathway. To obtain a genetic system for studying KSHV vFLIP mutation in the context of the viral genome, we generated recombinant viruses lacking the coding sequence (CDS) of vFLIP gene (K13/ORF71) by bacterial artificial chromosome (BAC) technology and the Escherichia coli Red recombination system. After a series of verification with PCR, restriction digestion and sequencing, the K13 deletion bacmids was transfected into a stable viral producer cell line based on iSLK cells to create vFLIP-knockout mutant. Importantly, human umbilical vein endothelial cells (HUVECs) could be de novo infected by vFLIP mutant virus, which are now available for studying the roles of vFLIP in regulation of other KSHV genes and viral pathogenesis.

show abstract

The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA

Cited by 44 publications

References 89 publications

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

Generation of a KSHV K13 deletion mutant for vFLIP function study

Contact Info

Product

Resources

About