Abstract：
BACKGROUND: Mitochondrial calcium uniporter (MCU) is a central subunit of MCU complex that regulate the levels of calcium ions within mitochondria. A comprehensive understanding the implications of MCU in clinical prognostication, biological understandings and therapeutic opportunity of breast cancer (BC) is yet to be determined.
OBJECTIVE: This study aims to investigate the role of MCU in predictive performance, tumor progression, epigenetic regulation, shaping of tumor immune microenvironment, and pharmacogenetics and the development of anti-tumor therapy for BC.
METHODS: The downloaded TCGA datasets were used to identify predictive ability of MCU expressions via supervised learning principle. Functional enrichment, mutation landscape, immunological profile, drug sensitivity were examined using bioinformatics analysis and confirmed by experiments exploiting human specimens, in vitro and in vivo models.
RESULTS: MCU copy numbers increase with MCU gene expression. MCU expression, but not MCU genetic alterations, had a positive correlation with known BC prognostic markers. Higher MCU levels in BC showed modest efficacy in predicting overall survival. In addition, high MCU expression was associated with known BC prognostic markers and with malignancy. In BC tumor and sgRNA-treated cell lines, enrichment pathways identified the involvement of cell cycle and immunity. miR-29a was recognized as a negative epigenetic regulator of MCU. High MCU levels were associated with increased mutation levels in oncogene TP53 and tumor suppression gene CDH1, as well as with an immunosuppressive microenvironment. Sigle-cell sequencing indicated that MCU mostly mapped on to tumor cell and CD8 T-cells. Inter-databases verification further confirmed the aforementioned observation. miR-29a-mediated knockdown of MCU resulted in tumor suppression and mitochondrial dysfunction, as well as diminished metastasis. Furthermore, MCU present pharmacogenetic significance in cellular docetaxel sensitivity and in prediction of patients\' response to chemotherapeutic regimen.
CONCLUSIONS: MCU shows significant implication in prognosis, outcome prediction, microenvironmental shaping and precision medicine for BC. miR-29a-mediated MCU inhibition exerts therapeutic effect in tumor growth and metastasis.
OBJECTIVE: This study aims to investigate the role of MCU in predictive performance, tumor progression, epigenetic regulation, shaping of tumor immune microenvironment, and pharmacogenetics and the development of anti-tumor therapy for BC.
METHODS: The downloaded TCGA datasets were used to identify predictive ability of MCU expressions via supervised learning principle. Functional enrichment, mutation landscape, immunological profile, drug sensitivity were examined using bioinformatics analysis and confirmed by experiments exploiting human specimens, in vitro and in vivo models.
RESULTS: MCU copy numbers increase with MCU gene expression. MCU expression, but not MCU genetic alterations, had a positive correlation with known BC prognostic markers. Higher MCU levels in BC showed modest efficacy in predicting overall survival. In addition, high MCU expression was associated with known BC prognostic markers and with malignancy. In BC tumor and sgRNA-treated cell lines, enrichment pathways identified the involvement of cell cycle and immunity. miR-29a was recognized as a negative epigenetic regulator of MCU. High MCU levels were associated with increased mutation levels in oncogene TP53 and tumor suppression gene CDH1, as well as with an immunosuppressive microenvironment. Sigle-cell sequencing indicated that MCU mostly mapped on to tumor cell and CD8 T-cells. Inter-databases verification further confirmed the aforementioned observation. miR-29a-mediated knockdown of MCU resulted in tumor suppression and mitochondrial dysfunction, as well as diminished metastasis. Furthermore, MCU present pharmacogenetic significance in cellular docetaxel sensitivity and in prediction of patients\' response to chemotherapeutic regimen.
CONCLUSIONS: MCU shows significant implication in prognosis, outcome prediction, microenvironmental shaping and precision medicine for BC. miR-29a-mediated MCU inhibition exerts therapeutic effect in tumor growth and metastasis.
摘要：
背景：线粒体钙单向蛋白（MCU）是MCU复合物的中心亚基，可调节线粒体内钙离子的水平。全面了解MCU在临床预后中的意义，乳腺癌（BC）的生物学理解和治疗机会尚未确定。
目的：本研究旨在探讨MCU在预测性能中的作用，肿瘤进展，表观遗传调控，肿瘤免疫微环境的塑造，和药物遗传学以及BC抗肿瘤治疗的发展。
方法：下载的TCGA数据集用于通过监督学习原理识别MCU表达式的预测能力。功能富集,突变景观，免疫学特征，使用生物信息学分析检查药物敏感性，并通过利用人体标本的实验证实，体外和体内模型。
结果：MCU拷贝数随着MCU基因表达而增加。MCU表达式,但不是MCU基因改变，与已知的BC预后标志物呈正相关。BC中较高的MCU水平在预测总生存率方面显示出适度的功效。此外,MCU高表达与已知的BC预后标志物和恶性肿瘤相关.在BC肿瘤和sgRNA处理的细胞系中，富集途径确定了细胞周期和免疫的参与。miR-29a被认为是MCU的负表观调节因子。高MCU水平与癌基因TP53和肿瘤抑制基因CDH1的突变水平增加以及免疫抑制微环境相关。Sigle细胞测序表明MCU主要映射到肿瘤细胞和CD8T细胞上。数据库间的核查进一步证实了上述观点。miR-29a介导的MCU敲低导致肿瘤抑制和线粒体功能障碍，以及减少转移。此外，MCU在细胞多西他赛敏感性和预测患者对化疗方案的反应方面具有药物遗传学意义。
结论：MCU对预后具有重要意义，结果预测，BC微环境整形和精准医学。miR-29a介导的MCU抑制在肿瘤生长和转移中发挥治疗作用。
目的：本研究旨在探讨MCU在预测性能中的作用，肿瘤进展，表观遗传调控，肿瘤免疫微环境的塑造，和药物遗传学以及BC抗肿瘤治疗的发展。
方法：下载的TCGA数据集用于通过监督学习原理识别MCU表达式的预测能力。功能富集,突变景观，免疫学特征，使用生物信息学分析检查药物敏感性，并通过利用人体标本的实验证实，体外和体内模型。
结果：MCU拷贝数随着MCU基因表达而增加。MCU表达式,但不是MCU基因改变，与已知的BC预后标志物呈正相关。BC中较高的MCU水平在预测总生存率方面显示出适度的功效。此外,MCU高表达与已知的BC预后标志物和恶性肿瘤相关.在BC肿瘤和sgRNA处理的细胞系中，富集途径确定了细胞周期和免疫的参与。miR-29a被认为是MCU的负表观调节因子。高MCU水平与癌基因TP53和肿瘤抑制基因CDH1的突变水平增加以及免疫抑制微环境相关。Sigle细胞测序表明MCU主要映射到肿瘤细胞和CD8T细胞上。数据库间的核查进一步证实了上述观点。miR-29a介导的MCU敲低导致肿瘤抑制和线粒体功能障碍，以及减少转移。此外，MCU在细胞多西他赛敏感性和预测患者对化疗方案的反应方面具有药物遗传学意义。
结论：MCU对预后具有重要意义，结果预测，BC微环境整形和精准医学。miR-29a介导的MCU抑制在肿瘤生长和转移中发挥治疗作用。
