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26 March 2019 : Laboratory Research  

Increased Expression of Exosomal AGAP2-AS1 (AGAP2 Antisense RNA 1) In Breast Cancer Cells Inhibits Trastuzumab-Induced Cell Cytotoxicity

Zhongqiu Zheng1ABCDEFG, Minlong Chen1B, Ping Xing1B, Xingqiang Yan1B, Bojian Xie1ABCDEFG*

DOI: 10.12659/MSM.915419

Med Sci Monit 2019; 25:2211-2220

Abstract

BACKGROUND: Trastuzumab therapy is important for patients with HER2-positive breast cancer, but more and more patients have experienced trastuzumab resistance during recent years. Accumulating evidence from recent studies showed that long non-coding RNAs (lncRNAs) play essential roles in chemoresistance of various cancer types, but the precise role of lncRNAs in trastuzumab resistance is unclear. In the present study, we aimed to identify the biofunction of lncRNA APAP2-AS1 in tranastuzumab resistance and to reveal the underlying regulatory mechanism.

MATERIAL AND METHODS: By culturing HER2-positive SKBR-3 and BT474 cells with transtuzumab-containing medium, we built trastuzumab-resistant cells. Quantitative real-time PCR was used to test the expression of AGAP2-AS1 in the built trastuzumab-resistant cells. Cell viability assay and TUNEL assay were used to test the cell viability and apoptosis in each group. Exosomes were purified from cells cultured in exosomes-depleted FBS and identified by transmission electron microscopy.

RESULTS: qRT-PCR assay suggested that AGAP2-AS1 was upregulated in the built trastuzumab-resistant cells when compared with parental sensitive cells. Cell viability assay showed that silencing of AGAP2-AS1 enhanced the cytotoxicity induced by trastuzumab treatment. Mechanistically, we revealed that AGAP2-AS1 was secreted outside cells by incorporation into exosomes in an hnRNPA2B1-dependent manner. More importantly, co-culture AGAP2-AS1-containing exosomes with sensitive cells reduced the trastuzumab-induced cell death, and silencing of AGAP2-AS1 from exosomes reversed this effect. In summary, AGAP2-AS1 promotes trastuzumab resistance of breast cancer cells through packaging into exosomes.

CONCLUSIONS: Knockdown of AGAP2-AS1 may be helpful for improving the clinical outcome for HER2+ breast cancer patients and could serve as a therapeutic target.

Keywords: Breast Neoplasms, exosomes, RNA, Long Noncoding, Apoptosis, Cell Proliferation, Drug Resistance, Neoplasm, transcriptional activation, Trastuzumab

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750