Exosome-mediated transfer of lncRNA‑SNHG14 promotes trastuzumab chemoresistance in breast cancer.

Abstract

Currently, resistance to trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor, has become an important obstacle to improving the clinical outcome of patients with advanced HER2+ breast cancer. While cell behavior may be modulated by long non‑coding RNAs (lncRNAs), the contributions of lncRNAs within extracellular vesicles (exosomes) are largely unknown. To this end, the involvement and regulatory functions of potential lncRNAs contained within exosomes during the formation of chemoresistance in human breast cancer were investigated. Trastuzumab-resistant cell lines were established by continuously grafting HER2+ SKBR-3 and BT474 cells into trastuzumab-containing culture medium. An lncRNA microarray assay followed by reverse transcription‑quantitative polymerase chain reaction analysis identified that lncRNA-small nucleolar RNA host gene 14 (SNHG14) was upregulated in trastuzumab-resistant cells when compared with parental breast cancer cells. Functional experimentation demonstrated that knockdown of lncRNA‑SNHG14 potently promoted trastuzumab-induced cytotoxicity. Furthermore, extracellular lncRNA‑SNHG14 was able to be incorporated into exosomes and transmitted to sensitive cells, thus disseminating trastuzumab resistance. Treatment of sensitive cells with exosomes highly expressing lncRNA‑SNHG14 induced trastuzumab resistance, while knockdown of lncRNA‑SNHG14 abrogated this effect. The Signal Transduction Reporter Array indicated that lncRNA‑SNHG14 may promote the effect of trastuzumab by targeting the apoptosis regulator Bcl‑2 (Bcl‑2)/apoptosis regulator BAX (Bax) signaling pathway. Furthermore, the expression level of serum exosomal lncRNA‑SNHG14 was upregulated in patients who exhibited resistance to trastuzumab, compared with patients exhibiting a response. Therefore, lncRNA‑SNHG14 may be a promising therapeutic target for patients with HER2+ breast cancer.

• Authors: Huaying Dong, Wei Wang, Ru Chen, Yu Zhang, Kejian Zou, Mulin Ye, Xionghui He, Fan Zhang, Jing Han
• Journal: International journal of oncology (Int J Oncol) Vol. 53 Issue 3 Pg. 1013-1026 (Sep 2018) ISSN: 1791-2423 [Electronic] Greece
• PMID: 30015837 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• Antineoplastic Agents, Immunological
• BAX protein, human
• BCL2 protein, human
• Biomarkers, Tumor
• MicroRNAs
• Proto-Oncogene Proteins c-bcl-2
• RNA, Long Noncoding
• RNA, Small Interfering
• bcl-2-Associated X Protein
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Aged
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Apoptosis (drug effects, genetics)
• Biomarkers, Tumor (blood, genetics, metabolism)
• Breast Neoplasms (blood, drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Drug Resistance, Neoplasm (genetics)
• Exosomes (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• MicroRNAs (metabolism)
• Middle Aged
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Long Noncoding (blood, genetics, metabolism)
• RNA, Small Interfering
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Signal Transduction (genetics)
• Trastuzumab (pharmacology, therapeutic use)
• Up-Regulation
• bcl-2-Associated X Protein (metabolism)