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RETRACTED ARTICLE: MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer

Oncogene volume 40, pages 833–847 (2021)Cite this article

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Abstract

Trastuzumab resistance has been becoming a major obstacle for treatment of HER-2-positive breast cancer patients. Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this study, mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as human antigen R (HuR), miR-15a-5p, and carnitine palmitoyl transferase 1 (CPT1). In vitro and in vivo experimental assays were done to clarify the functional role of AGAP2-AS1 in trastuzumab resistance, stemness, and fatty acid oxidation (FAO). The results showed that MSC co-culture induced trastuzumab resistance. AGAP2-AS1 was upregulated in MSC-cultured cells, and knockdown of AGAP2-AS1 reversed the MSC-mediated trastuzumab resistance. Furthermore, MSC culture-induced AGAP2-AS1 regulates stemness and trastuzumab resistance via activating FAO. Mechanistically, AGAP2-AS1 is associated with HuR, and the AGAP2-AS1–HuR complex could directly bind to the CPT1, increasing its expression via improving RNA stability. In addition, AGAP2-AS1 could serve as ceRNA via sponging miR-15a-5p and releasing CPT1 mRNA. Clinically, increased expression of serum AGAP2-AS1 predicts poor response to trastuzumab treatment in breast cancer patients. In conclusion, MSC culture-induced AGAP2-AS1 caused stemness and trastuzumab resistance via promoting CPT1 expression and inducing FAO. Our results provide new insight of the role of MSCs in trastuzumab resistance and AGAP2-AS1 could be promising predictive biomarker and therapeutic target for HER-2+ breast cancer patients.

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Fig. 1: MSC induced stemness and trastuzumab resistance in BC cells.
Fig. 2: MSCs regulates trastuzumab resistance via upregulation of AGAP2-AS1 expression.
Fig. 3: AGAP2-AS1-mediated MSC-induced stemness and trastuzumab resistance via regulating FAO.
Fig. 4: AGAP2-AS1 is associated with HuR protein.
Fig. 5: AGAP2-AS1–HuR complex promotes the stability of CPT1 mRNA.
Fig. 6: AGAP2-AS1 sponges miR-15a-5p and releasing CPT1 expression.
Fig. 7: AGAP2-AS1 facilitate stemness and trastuzumab resistance in vivo.
Fig. 8: Serum AGAP2-AS1 predicts response to trastuzumab treatment of BC patients.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Professor Manran Liu, The Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China, for critical technical support.

Funding

This study is supported by National Natural Science Foundation of China (81960475, 82072932) and The “Nanhai series” talent cultivation program of Hainan Province.

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Author notes

  1. These authors contributed equally: Jing Han, Hongbo Qu, Mingli Han.

Authors and Affiliations

  1. Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311, Haikou, China

    Jing Han, Yichao Ding, Mingwei Xie & Huaying Dong

  2. Department of Breast and Thyroid Surgery, The First People’s Hospital of Chenzhou City, 423000, Hunan, China

    Hongbo Qu

  3. Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China

    Mingli Han

  4. Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, 400010, Chongqing, China

    Jianguo Hu

  5. Department of General Surgery, Chongqing Renji Hospital, University of Chinese Academy of Science, Chongqing, China, 400062, Chongqing, China

    Yuanwen Chen

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Han, J., Qu, H., Han, M. et al. RETRACTED ARTICLE: MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer. Oncogene 40, 833–847 (2021). https://doi.org/10.1038/s41388-020-01574-8

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