RETRACTED ARTICLE: Exosome-mediated lncRNA AFAP1-AS1 promotes trastuzumab resistance through binding with AUF1 and activating ERBB2 translation

Abstract

Background: Although 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.Methods: LncRNA 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.Results: AFAP1-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.Conclusion: Exosomal 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.

PGM5-AS1 Inhibits the Malignant Phenotype of Colon Cancer Cells by Regulating PAEP and NME1

“…According to previous studies, abnormally high expression of lncRNA may be induced by transcription activators, stress, DNA methylation, and exosomes [47][48][49][50][51]. For example, the tumor suppressor gene p53 can transcriptionally activate lncRNA Pvt1b [47].…”

“…Upregulation of lncRNA SNHG12, mediated by DNA methylation, thereby activating and increasing temozolomide resistance in glioblastoma [50]. Exosome-mediated lncRNA AFAP1-AS1 activates ERBB2 translation [51]. However, few studies have explored the mechanism underlying the abnormally low expression of lncRNA.…”

Exosomal lncRNA OIP5-AS1 confers cells trastuzumab resistance in breast cancer through miR-381-3p/HMGB3 axis

“…In breast cancer, the effects of exosomal lncRNA in drug resistance were also demonstrated. For instance, exosome-mediated transfer of AFAP1-AS1 induced trastuzumab resistance in breast cancer via the interaction with AUF1 and the activation of ERBB2 translation [26]. Intercellular transfer of lncRNA H19 promoted doxorubicin resistance in breast cancer [27].…”

Exosomal Long Noncoding Rna AGAP2-AS1 Regulates Trastuzumab Resistance via Inducing Autophagy in Breast Cancer

“…More recently, emerging evidence has indicated that exosomes regulate malignancyby transferring multiple classes of cargo molecules to recipient cells to mediateintercellular communication, including lncRNAs. Exosomal lncRNAs participate in tumor formation,proliferation, metastasis and chemotherapy resistance by regulating oncogenes ortumor suppressor genes [9,36,37]. However, communication in BC cells withdifferent drug response via exosomes is obscured.…”