Abstract 65P
Background
Radiation injury of blood vessels (RIBV) is a serious long-term complication of radiotherapy, and the main pathophysiological change of which is atherosclerosis. Senescence of vascular smooth muscle cells (VSMCs) is implicated in the pathogenesis of radiation-induced atherosclerosis. The mechanisms underlying VSMCs senescence, however, remain poorly understood.
Methods
Using cultured human aortic smooth cells (HASMC) and SD male explored whether IR could induce transformation of senescent phenotype of VSMCs. ChIP assay explored whether SICC bind to p16 gene in irradiated cells. SA-β-gal staining indicate radiation-induced senescence.
Results
Using cultured human aortic smooth cells (HASMC) and SD male rats showed that IR could induce transformation of senescent phenotype of VSMCs with significant positive dose and time dependence in vitro and in vivo. IR activated DDR/NF-κB pathway and induced the nuclear loss of HMGB2 and thus spatial aggregation of CTCF, known as senescence-induced CTCF clusters (SICC), but had no significant effect on the expression level of CTCF. And ChIP assay showed that SICC exhibited stronger binding ability to p16 gene in irradiated cells. Overexpressing HMGB2 and silencing CTCF abrogated radiation-stimulated p16 upregulation with less SICC formation. Suppression of the activation of NF-κB by PDTC (a common inhibitor of NF-κB) attenuated radiation-induced senescence, indicated by less SA-β-gal staining, downregulation of p16. We also found that PDTC reduced radiation-induced nuclear loss of HMGB2 and formation of SICC.
Conclusions
In summary, we demonstrated here, for the first time, that IR induced transformation of senescent phenotype of VSMCs in vivo and in vitro, and activated NF-κB pathway to initiate HMGB2 nuclear loss and thus promote the formation of SICC, which further strengthen the binding ability of CTCF and p16 gene, and resulted in the occurrence of radiation-induced senescence in VSMCs. These findings may have a significant impact on the research of radiation-induced atherosclerosis and open a new prospective in the prevention and therapeutic intervention in RIBV.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
78P - Peroxiredoxin-1 knockout negatively affects the viability of ph+ B-cell acute lymphoblastic leukemia cells and sensitizes them to tyrosine kinase inhibitors
Presenter: Jaromir Hunia
Session: Poster session 09
79P - Co-delivered crizotinib and gefitinib based on nanoparticle for synergically overcoming resistance lung adenocarcinoma treatment
Presenter: Haiyu Zhou
Session: Poster session 09
80P - Steroidal oximes: A new potential therapeutic approach for cancer treatment
Presenter: Mafalda Laranjo
Session: Poster session 09
81P - miR-23b and -133a role on TRAIL-induced apoptosis pathway components expression and TRAIL sensitization in lung adenocarcinoma cells
Presenter: Denise Leite
Session: Poster session 09
83P - Impact of VHL-associated tumor treatment on mental health: An international patient survey
Presenter: Othon Iliopoulos
Session: Poster session 09
84P - Microenvironment immune differences between sexes in multiple myeloma
Presenter: Maria de los Angeles Clavo
Session: Poster session 09
85P - In silico evaluation of the transcriptomic and immunologic profile of lung adenocarcinomas with deletions or disruptive mutations of SMARCA4
Presenter: Ester Garcia Lorenzo
Session: Poster session 09
86P - Effect of chemotherapy-induced autophagic secretome on natural killer cell activity
Presenter: Ayfer Karlitepe
Session: Poster session 09
87P - WIP1 phosphatase promotes etoposide induced autophagy in medulloblastoma and neuroblastoma
Presenter: Hatice Pilevneli
Session: Poster session 09
88P - PPM1D/WIP1 phosphatase mediates basal and genotoxic stress-induced autophagy via ULK-1 de-phosphorylation
Presenter: Ceylan Ak
Session: Poster session 09