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

Mingli Han1, Yuanting Gu2, Pengwei Lu2

  • 1Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. minglihan@126.com.

Molecular Cancer
|February 6, 2020
PubMed
Abstract

Insights

Long noncoding RNA AFAP1-AS1 promotes trastuzumab resistance in breast cancer by enhancing ERBB2 translation. Targeting exosomal AFAP1-AS1 may offer a new strategy for overcoming treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Trastuzumab is effective for HER2-positive breast cancer but resistance limits its clinical benefit.
  • Long noncoding RNAs (lncRNAs) are implicated in cancer development and chemoresistance.
  • The role of lncRNAs in trastuzumab resistance remains poorly understood.

Purpose of the Study:

  • To identify differentially expressed lncRNAs in trastuzumab-resistant breast cancer.
  • To investigate the regulatory mechanism of a specific lncRNA, AFAP1-AS1, in trastuzumab resistance.
  • To explore the potential of AFAP1-AS1 as a predictive biomarker for treatment response.

Main Methods:

  • LncRNA microarray and qRT-PCR to identify dysregulated lncRNAs.
  • Transmission electron microscopy and ultracentrifugation to characterize exosomal AFAP1-AS1.
  • Bioinformatics, RNA-FISH, and immunoprecipitation assays to determine molecular interactions.
  • Functional assays (gain/loss) to confirm the role of AFAP1-AS1 in trastuzumab resistance.

Main Results:

  • AFAP1-AS1 expression was significantly higher in trastuzumab-resistant cells and associated with poorer patient outcomes.
  • Knockdown of AFAP1-AS1 reversed trastuzumab resistance, indicating its crucial role.
  • Exosomal AFAP1-AS1 secreted by resistant cells conferred resistance to recipient cells.
  • AFAP1-AS1 promotes ERBB2 translation via interaction with AUF1, independent of mRNA levels.

Conclusions:

  • Exosomal AFAP1-AS1 induces trastuzumab resistance by promoting ERBB2 translation through AUF1.
  • AFAP1-AS1 levels may serve as a predictive marker for trastuzumab resistance in breast cancer.
  • Targeting AFAP1-AS1 presents a potential therapeutic strategy to overcome trastuzumab resistance.
Keywords:
AFAP1-AS1Breast cancerERBB2ExosomeTrastuzumab resistance

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