Dataset Information

Nanoparticles (NPs)-Meditated LncRNA AFAP1-AS1 Silencing to Block Wnt/?-Catenin Signaling Pathway for Synergistic Reversal of Radioresistance and Effective Cancer Radiotherapy.

ABSTRACT: 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/?-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.

SUBMITTER: Bi Z

PROVIDER: S-EPMC7509644 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Nanoparticles (NPs)-Meditated LncRNA AFAP1-AS1 Silencing to Block Wnt/<i>β</i>-Catenin Signaling Pathway for Synergistic Reversal of Radioresistance and Effective Cancer Radiotherapy.

Bi Zhuofei Z Li Qingjian Q Dinglin Xiaoxiao X Xu Ying Y You Kaiyun K Hong Huangming H Hu Qian Q Zhang Wei W Li Chenchen C Tan Yujie Y Xie Ning N Ren Wei W Li Chuping C Liu Yimin Y Hu Hai H Xu Xiaoding X Yao Herui H

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200805 18

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 ho ...[more]

PMID: 32999837

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Project description:BackgroundAlthough trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the emergence of resistance. Recent evidence suggests that long noncoding RNAs (lncRNAs) play important roles in tumorigenesis and chemoresistance. However, the regulatory mechanism of lncRNAs in trastuzumab resistance is not well established to date. In this research, we identified the differentially expressed lncRNA and investigated its regulatory role in trastuzumab resistance of breast cancer.MethodsLncRNA microarray and qRT-PCR were performed to identify the dysregulated lncRNAs. Transmission electron microscopy, differential ultracentrifugation and qRT-PCR were used to verify the existence of exosomal AFAP1-AS1 (actin filament associated protein 1 antisense RNA 1). Bioinformatics prediction, RNA fluorescence in situ hybridization (RNA-FISH) and immunoprecipitation assays were performed to identify the direct interactions between AFAP1-AS1 and other associated targets, such as AU-binding factor 1 (AUF1) and ERBB2. Finally, a series gain- or loss-functional assays were done to prove the precise role of AFAP1-AS1 in trastuzumab resistance.ResultsAFAP1-AS1 was screened out due to its higher expression in trastuzumab-resistant cells compared to sensitive cells. Increased expression of AFAP1-AS1was associate with poorer response and shorter survival time of breast cancer patients. AFAP1-AS1 was upregulated by H3K27ac modification at promoter region, and knockdown of AFAP1-AS1 reversed trastuzumab resistance. Moreover, extracellular AFAP1-AS1 secreted from trastuzumab resistant cells was packaged into exosomes and then disseminated trastuzumab resistance of receipt cells. Mechanically, AFAP1-AS1 was associated with AUF1 protein, which further promoted the translation of ERBB2 without influencing the mRNA level.ConclusionExosomal AFAP1-AS1 could induce trastuzumab resistance through associating with AUF1 and promoting ERBB2 translation. Therefore, AFAP1-AS1 level may be useful for prediction of trastuzumab resistance and breast cancer treatment.

Dataset Information

Nanoparticles (NPs)-Meditated LncRNA AFAP1-AS1 Silencing to Block Wnt/?-Catenin Signaling Pathway for Synergistic Reversal of Radioresistance and Effective Cancer Radiotherapy.

Publications

Nanoparticles (NPs)-Meditated LncRNA AFAP1-AS1 Silencing to Block Wnt/<i>β</i>-Catenin Signaling Pathway for Synergistic Reversal of Radioresistance and Effective Cancer Radiotherapy.

Similar Datasets

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