期刊
ADVANCED SCIENCE
卷 7, 期 18, 页码 -出版社
WILEY
DOI: 10.1002/advs.202000915
关键词
cancer radiotherapy; lncRNAs; nanoparticles; radioresistance; Wnt/beta-catenin signaling pathway
资金
- National Science and Technology Major Project [2020ZX09201021]
- National Natural Science Foundation of China [81572596, 81874226, 81972471, U1601223]
- Thousand Talents Program for Distinguished Young Scholars
- International Scientific and Technological Cooperation Program from Guangdong Science and Technology Department [2018A050506033]
- Natural Science Foundation of Guangdong Province [2017A030313828, 2016A030313312]
- Guangzhou Science and Technology Major Program [201704020131]
- Guangzhou Science and Technology Bureau [201902020015]
- Fundamental Research Funds for the Central Universities of China
- Three million for Three Years Project of the High-level Talent Special Funding Scheme of Sun Yat-Sen Memorial Hospital
- Sun Yat-Sen University Clinical Research 5010 Program [2018007]
- Sun Yat-Sen Clinical Research Cultivating Program [SYS-C-201801]
- China Postdoctoral Science Foundation [2019M663288]
- Guangdong Science and Technology Department [2017B030314026]
Resistance to radiotherapy is frequently encountered in clinic, leading to poor prognosis of cancer patients. Long noncoding RNAs (lncRNAs) play important roles in the development of radioresistance due to their functions in regulating the expression of target genes at both transcriptional and posttranscriptional levels. Exploring key lncRNAs and elucidating the mechanisms contributing to radioresistance are crucial for the development of effective strategies to reverse radioresistance, which however remains challenging. Here, actin filament-associated protein 1 antisense RNA1 (lncAFAP1-AS1) is identified as a key factor in inducing radioresistance of triple-negative breast cancer (TNBC) via activating the Wnt/beta-catenin signaling pathway. Considering the generation of a high concentration of reduction agent glutathione (GSH) under radiation, a reduction-responsive nanoparticle (NP) platform is engineered for effective lncAFAP1-AS1 siRNA (siAFAP1-AS1) delivery. Systemic delivery of siAFAP1-AS1 with the reduction-responsive NPs can synergistically reverse radioresistance by silencing lncAFAP1-AS1 expression and scavenging intracellular GSH, leading to a dramatically enhanced radiotherapy effect in both xenograft and metastatic TNBC tumor models. The findings indicate that lncAFAP1-AS1 can be used to predict the outcome of TNBC radiotherapy and combination of systemic siAFAP1-AS1 delivery with radiotherapy can be applied for the treatment of recurrent TNBC patients.
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