Nanoparticles (NPs)‐Meditated LncRNA AFAP1‐AS1 Silencing to Block Wnt/β‐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/β‐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.

SMG9 Serves as an Oncogene to Promote the Tumor Progression via EMT and Wnt/β-Catenin Signaling Pathway in Hepatocellular Carcinoma

“…Meanwhile, there is a strong connection between EMT and HCC (Tong et al, 2020). The Wnt/β-catenin signaling pathway is involved in the development of various human cancers and one of the most well-characterized oncogenic pathway in HCC (Hoshida et al, 2009;Huang et al, 2019;Bi et al, 2020;Wang et al, 2020). A variety of key cellular processes including proliferation, apoptosis, migration and invasion are involved in the progression of HCC in a Wnt/β-catenin-dependent manner (Huang et al, 2020;Lin et al, 2020).…”

The long non‐coding RNA landscape in triple‐negative breast cancer

“…18 operative radiotherapy. 138 They also found higher lncAFAP1-AS1 expression was correlated with poor disease-free survival and overall survival of TNBC patients. 138 These results demonstrated that high lncAFAP1-AS1 expression is associated with radio-resistance of TNBC patients, and the expression level of lncAFAP1-AS1 in tumour tissues could be used to predict the outcome of TNBC radiotherapy.…”

“…Recently, Bi et al reported that higher lncAFAP1‐AS1 expression was detected in the patients with local recurrence, using the surgically resected tumour tissues of TNBC patients receiving postoperative radiotherapy 138 138 . These results demonstrated that high lncAFAP1‐AS1 expression is associated with radio‐resistance of TNBC patients, and the expression level of lncAFAP1‐AS1 in tumour tissues could be used to predict the outcome of TNBC radiotherapy.…”

Long Noncoding RNAs Regulate the Radioresistance of Breast Cancer

“…Upregulation of AFAP1-AS1 promotes BRCA cell proliferation and invasion but inhibits cell apoptosis in vitro, while overexpression of AFAP1-AS1 promotes tumor growth in vivo and is associated with poor prognosis of TNBC patients [ 82 ]. Bi et al [ 83 ] selected AFAP1-AS1 from the locally recurrent BRCA samples after RT and the radioresistant BRCA cell line MDA-MB-231. They discovered that lncAFAP1-AS1 was not only upregulated in radioresistant cells and tumor tissues but was also associated with a low survival rate of BRCA patients from the TCGA database.…”