Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
Cancer Res. 2019 Apr 1;79(7):1520-1534. doi: 10.1158/0008-5472.CAN-18-0891. Epub 2019 Feb 8.
Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor-immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis. SIGNIFICANCE: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.
各种 miRNA 在实体瘤的发生和发展中起着关键作用。在这项研究中，我们描述了 miR-204-5p 在限制乳腺癌生长和进展中的作用。与正常乳腺组织相比，乳腺癌组织中 miR-204-5p 显著下调，其表达水平与乳腺癌患者的生存结果增加相关。miR-204-5p 的过表达抑制了人源和鼠源乳腺癌细胞的活力、增殖和迁移能力。此外，miR-204-5p 的过表达导致癌细胞代谢特性发生显著改变，并抑制了小鼠乳腺癌模型中的肿瘤生长和转移。miR-204-5p 表达与乳腺癌患者临床结局之间的相关性呈非线性模式，在癌细胞行为和转移能力的实验研究中得到了重现。转录组和蛋白质组分析显示，包括 PI3K/Akt 和肿瘤免疫相互作用在内的各种癌症相关途径与 miR-204-5p 的表达显著相关。PI3K/Akt 途径的主要调节因子 PIK3CB 是 miR-204-5p 的直接靶点，PIK3CB 相关的 PI3K/Akt 信号与 miR-204-5p 之间的关联在基底亚型中最为明显。乳腺癌细胞对包括 PI3K 抑制剂在内的各种抗癌药物的敏感性受 miR-204-5p 表达的显著影响。此外，miR-204-5p 调节肿瘤细胞中关键细胞因子的表达，并通过改变髓系和淋巴细胞群体重新编程免疫微环境。这些数据表明，肿瘤抑制因子 miR-204-5p 在乳腺癌的发生和转移中具有细胞自主和非细胞自主的影响。意义：本研究表明，miR-204-5p 对 PI3K/Akt 信号的调节抑制了乳腺癌的转移和免疫细胞的重编程。
