MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer (Retracted Article)
MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer (Retracted Article)
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DOI：
10.1038/s41388-020-01574-8
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发表时间：
2020-12-03
期刊：
影响因子：
8
通讯作者：
Dong, Huaying
中科院分区：
文献类型：
--
作者：
Han, Jing;Qu, Hongbo;Dong, Huaying
曲妥珠单抗耐药已成为her -2阳性乳腺癌患者治疗的主要障碍。越来越多的证据表明，间充质干细胞（MSCs）在耐药性形成过程中起着至关重要的作用，然而，其潜在的机制尚不清楚。本研究采用质谱法、RNA下拉法和RNA免疫沉淀法验证AGAP2-AS1与其他相关靶标（如人抗原R （HuR）、miR-15a-5p和肉毒碱棕榈酰转移酶1 (CPT1)）之间的直接相互作用。通过体外和体内实验分析，阐明AGAP2-AS1在曲妥珠单抗耐药、干性和脂肪酸氧化（FAO）中的功能作用。结果显示MSC共培养诱导曲妥珠单抗耐药。AGAP2-AS1在msc培养的细胞中上调，AGAP2-AS1的下调逆转了msc介导的曲妥珠单抗耐药。此外，MSC培养诱导的AGAP2-AS1通过激活FAO来调节干细胞的干性和曲妥珠单抗耐药性。机制上，AGAP2-AS1与HuR相关，AGAP2-AS1-HuR复合体可以直接结合到CPT1上，通过提高RNA的稳定性来增加其表达。此外，AGAP2-AS1可以通过海绵化miR-15a-5p并释放CPT1 mRNA作为ceRNA。在临床上，血清AGAP2-AS1表达升高预示着乳腺癌患者对曲妥珠单抗治疗的不良反应。综上所述，MSC培养诱导的AGAP2-AS1通过促进CPT1表达和诱导FAO而引起细胞的干性和曲妥珠单抗耐药。我们的研究结果为MSCs在曲妥珠单抗耐药中的作用提供了新的见解，AGAP2-AS1可能是HER-2+乳腺癌患者有希望的预测性生物标志物和治疗靶点。
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.