Combination of Small Extracellular Vesicle-Derived Annexin A2 Protein and mRNA as a Potential Predictive Biomarker for Chemotherapy Responsiveness in Aggressive Triple-Negative Breast Cancer.
Combination of Small Extracellular Vesicle-Derived Annexin A2 Protein and mRNA as a Potential Predictive Biomarker for Chemotherapy Responsiveness in Aggressive Triple-Negative Breast Cancer.
复制标题
作者：
三阴性乳腺癌（TNBC）是一种高度侵袭性的疾病。它的特点是缺乏雌激素受体（ER），孕激素受体（PR）和人表皮生长因子受体2（HER 2）。因此，用靶向疗法治疗TNBC患者并具有用于治疗反应的生物标志物一直是医学领域专家的挑战。TNBC患者肿瘤具有膜联蛋白A2（AnxA 2）蛋白和mRNA的高表达。在这项研究中，我们证明了AnxA 2蛋白和mRNA在TNBC的后期阶段与小细胞外囊泡（sEV）高度相关，这在TNBC患者中以更好的治疗反应为标志。因此，我们引入sEV衍生的AnxA 2蛋白和mRNA作为TNBC中新辅助化疗反应的组合生物标志物。 小细胞外囊泡（sEV），主要是外泌体，是作为多泡体的管腔内囊泡从膜脱落的纳米囊泡，用作运载在调节肿瘤微环境以用于癌症转移的多步骤过程中有影响的货物的媒介物。膜联蛋白A2（AnxA 2）是一种钙（Ca 2+）依赖性磷脂结合蛋白，是sEV货物之一。sEV衍生的AnxA 2（sEV-AnxA 2）蛋白参与三阴性乳腺癌（TNBC）的转移过程。本研究的目的是确定sEV-AnxA 2蛋白和/或mRNA是否可以作为预测TNBC化疗反应性的有用生物标志物。从血清中去除免疫球蛋白G（IgG）以及使用System Bioscience的ExoQuick Ultra试剂盒，与超离心法相比，可有效分离sEV并检测sEV-AnxA 2蛋白和mRNA。将标准化方法应用于20个TNBC患者血清用于sEV分离。高水平的sEV-AnxA 2蛋白和/或mRNA与TNBC中的3期及以上相关。4例对新辅助化疗有反应的患者sEVs中AnxA 2蛋白和/或mRNA表达较高，而另外4例对化疗无反应的患者sEVs中AnxA 2蛋白和mRNA表达较低。我们的数据表明，sEV-AnxA 2蛋白和mRNA可能是侵袭性TNBC对化疗反应性的联合预测生物标志物。
Triple-negative breast cancer (TNBC) is a highly aggressive disease. It is marked by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Thus, treating TNBC patients with targeted therapy and having a biomarker for therapy response has always been a challenge for medical field experts. TNBC patient tumors have high expression of Annexin A2 (AnxA2) protein and mRNA. Here in this study, we demonstrate that the AnxA2 protein and mRNA highly associate with small extracellular vesicles (sEVs) at the later stages of TNBC which is marked by a better treatment response in TNBC patients. Thus, we introduce sEV-derived AnxA2 protein and mRNA as a combined biomarker for neo-adjuvant chemotherapy response in TNBC. Small extracellular vesicles (sEVs), mainly exosomes, are nanovesicles that shed from the membrane as intraluminal vesicles of the multivesicular bodies, serve as vehicles that carry cargo influential in modulating the tumor microenvironment for the multi-step process of cancer metastasis. Annexin A2 (AnxA2), a calcium(Ca2+)-dependent phospholipid-binding protein, is among sEV cargoes. sEV-derived AnxA2 (sEV-AnxA2) protein is involved in the process of metastasis in triple-negative breast cancer (TNBC). The objective of the current study is to determine whether sEV-AnxA2 protein and/or mRNA could be a useful biomarkers to predict the responsiveness of chemotherapy in TNBC. Removal of Immunoglobulin G (IgG) from the serum as well as using the System Bioscience’s ExoQuick Ultra kit resulted in efficient sEV isolation and detection of sEV-AnxA2 protein and mRNA compared to the ultracentrifugation method. The standardized method was applied to the twenty TNBC patient sera for sEV isolation. High levels of sEV-AnxA2 protein and/or mRNA were associated with stage 3 and above in TNBC. Four patients who responded to neoadjuvant chemotherapy had high expression of AnxA2 protein and/or mRNA in sEVs, while other four who did not respond to chemotherapy had low levels of AnxA2 protein and mRNA in sEVs. Our data suggest that the sEV-AnxA2 protein and mRNA could be a combined predictive biomarker for responsiveness to chemotherapy in aggressive TNBC.