Role of TLR9 in Oncogenic Virus-Produced Cancer

Martínez-Campos, Cecilia; Burguete-GarcíaAna, I; Madrid-MarinaVicente,

doi:10.1089/vim.2016.0103

Cited by 47 publications

(33 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TLR9 is expressed intracellularly, within the endosomal compartments, and functions to initiate proinflammatory response following activation. [33][34][35] Both HMGB1 and DNA can bind to RAGE directly and HMGB1 is expected to change the DNA binding properties to RAGE and facilitate DNA internalization. [36][37][38] However, it is not conclusive on how HMGB1 facilitates this transportation; either HMGB1 binds RAGE to increase the permeability of RAGE to nucleotides or HMGB1 binds FIGURE 8.…”

Section: Discussionmentioning

confidence: 99%

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

Tian

Charles

Yan

et al. 2019

The Journal of Thoracic and Cardiovascular Surgery

View full text Add to dashboard Cite

Introduction: Damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA), play critical roles in mediating ischemia-reperfusion injury (IRI). HMGB1 activates RAGE to exacerbate IRI, but the mechanism underlying cfDNA-induced myocardial IRI remains unknown. We hypothesized that the infarct-exacerbating effect of cfDNA is mediated by HMGB1 and receptor for advanced glycation end products (RAGE).Methods: C57BL/6 wild type mice, RAGE knockout (KO), and Toll-like receptor 9 KO mice underwent 20-or 40-minute occlusions of the left coronary artery followed by up to 60 minutes of reperfusion. Cardiac coronary perfusate was acquired from ischemic hearts without reperfusion. Exogenous mitochondrial DNA was acquired from livers of normal C57BL/6 mice. Myocardial infarct size (IS) was reported as percent risk region, as measured by 2,3,5-triphenyltetrazolium chloride and Phthalo blue (Heucotech, Fairless Hill, Pa) staining. cfDNA levels were measured by Sytox Green assay (Thermo Fisher Scientific, Waltham, Mass) and/or spectrophotometer.Results: Free HMGB1 and cfDNA levels were increased in the ischemic myocardium during prolonged ischemia and subsequently in the plasma during reperfusion. In C57BL/6 mice undergoing 40 0 /60 0 IRI, deoxyribonuclease I, or anti-HMGB1 monoclonal antibody reduced IS by approximately half to 29.0% AE 5.2% and 24.3% AE 3.5% (P < .05 vs control 54.3% AE 3.4%). However, combined treatment with deoxyribonuclease I þ anti-HMGB1 monoclonal antibody did not further attenuate IS (29.3% AE 4.9%). In C57BL/6 mice undergoing 20 0 /60 0 IRI, injection of 40 0 /5 0 plasma upon reperfusion increased IS by more than 3-fold (to 19.9 AE 4.3; P < .05). This IS exacerbation was abolished by pretreating the plasma with deoxyribonuclease I or by depleting the HMGB1 by immunoprecipitation, or by splenectomy. The infarct-exacerbating effect also disappeared in RAGE KO mice and Toll-like receptor 9 KO mice. Injection of 40 0 /0 0 coronary perfusate upon reperfusion similarly increased IS. The levels of HMGB1 and cfDNA were significantly elevated in the 40 0 /0 0 coronary perfusate and 40 0 /reperfusion (min) plasma but not in those with 10 0 ischemia. In C57BL/6 mice without IRI, 40 0 /5 0 plasma significantly increased the interleukin-1b protein and messenger RNA expression in the spleen by Schematic mechanism of the HMGB1-cfDNA complex in acute myocardial ischemia/reperfusion injury. Central MessageHMGB1 and cfDNA are released from the heart upon reperfusion after ischemia and contribute importantly and interdependently to the reperfusion injury by a common RAGE-TLR9-dependent mechanism.Perspective HMGB1 and cfDNA are released from infarcted myocardium into the bloodstream during reperfusion and mediate inflammatory response and exacerbate infarct size via activating splenic RAGE-TLR9 pathway. Depletion of either HMGB1 or cfDNA upon reperfusion suffices to abrogate the reperfusion injury. These results will help to develop novel therapeutical strategies to reduce myocard...

show abstract

Section: Discussionmentioning

confidence: 99%

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

Tian

Charles

Yan

et al. 2019

The Journal of Thoracic and Cardiovascular Surgery

View full text Add to dashboard Cite

show abstract

“…TLR9 binds the DNA of viruses and bacteria. It can trigger signaling cascades for a pro-inflammatory cytokine response [6,7]. Cancer and tissue damage can modulate TLR9 expression and activation [8,9].…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 9 negatively related to clinical outcome of AML patients

Al-Kahiry

Dammag

Abdelsalam

et al. 2020

J Egypt Natl Canc Inst

View full text Add to dashboard Cite

Background: Acute myeloid leukemia (AML) can modulate toll-like receptor-9 (TLR9) expression and activation. This study was conducted to elucidate the expression of TLR9 in AML patients and its relation to the prognosis of the disease. Results: The study included 40 newly diagnosed AML patients managed in the hospital in addition to 20 sex and age matched normal volunteers as control. TLR9 expression assay was conducted on peripheral blood samples of AML cases before the start of treatment as well as the controls by immunophenotyping. TLR9 expression was ranging from 0.10 to 2.40% in AML patients with higher expression among the control, ranging from 0.94 to 8.25%. The median TLR9 expression in AML patients was significantly lower with advanced cytogenetic risk score. It is not significantly differing in relation to patients' sex, age group, and FAB type of AML. However, significant lower median expression was found in relation to clinical outcome. TLR9 expression ≤ 1% showed lower median overall survival time when compared to those with > 1% expression. Conclusion: This study concluded that AML patients express TLR9 in leukemic cells with very low percentage. This expression was negatively related to the clinical outcome.

show abstract

“…Our results are consistent with these findings and suggest that ADV infection could trigger TLR9-MYD88 signaling and lead to the formation of GSCs from primary glioma cells in a STAT3-dependent way. However, in our system, CpG-ODN appeared not able to trigger the stemness signaling in glioma cells, although it has been widely employed as an agonist of TLR9 56 . More detailed dissecting of the signaling pathway downstream to TLR9 is required to clarify this inconsistency.…”

Section: Discussionmentioning

confidence: 72%

“…When triggered by its ligands such as viral DNA, TLR9 signaling initiate immune response by producing cytokines and type I interferons through MYD88, which interacts with IL1R-associated kinase 4 (IRAK4) and activate NF-kB and the MAPKs pathways, and the type I IFN pathway 56 . These signaling pathways lead to and reinforce inflammatory responses in TME, and indirectly promote stemness of cancer cells 22 .…”

Section: Discussionmentioning

confidence: 99%

Adenovirus infection promotes the formation of glioma stem cells by glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

Zang

Zheng

Cao

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundGlioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells, but the identity of the signaling molecules and underlying mechanisms have been incompletely elucidated.MethodsHuman samples and glioma cell lines were cultured in vitro to determine the effects of viral infection by sphere formation, qRT-PCR, Western blot, FACS and immunofluorescence; for in vivo analysis, mice subcutaneous tumor model was carried; while bioinformatics analysis and qRT-PCR were applied for further mechanistic studies.ResultsIn this study, we show that infection of patient-derived glioma cells with adenovirus (ADV) increases the formation of tumor spheres. ADV infection upregulated stem cell markers, and the resultant tumor spheres held the capacities of self-renewal and multi-lineage differentiation, and had stronger potential to form xenograft tumors in immune-compromised mice. ADV promoted GSC formation likely via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1, which is downstream to TLRs and play important roles in cancer stem cells via multiple mechanisms including strengthening STAT3 signaling. Indeed, knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, we show that HMGB1, a damage associated molecular pattern (DAMP) that also triggers TLR signaling, upregulated stemness markers in glioma cells.ConclusionsIn summary, our data indicate that ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.

show abstract

Role of TLR9 in Oncogenic Virus-Produced Cancer

Cited by 47 publications

References 83 publications

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

Toll-like receptor 9 negatively related to clinical outcome of AML patients

Adenovirus infection promotes the formation of glioma stem cells by glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

Contact Info

Product

Resources

About