Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan.
Breast Cancer Res Treat. 2012 Aug;134(3):1081-93. doi: 10.1007/s10549-012-2034-4. Epub 2012 Apr 4.
Tumor recurrence and metastasis result in an unfavorable prognosis for cancer patients. Recent studies have suggested that specific microRNAs (miRNAs) may play important roles in the development of cancer cells. However, prognostic markers and the outcome prediction of the miRNA signature in breast cancer patients have not been comprehensively assessed. The aim of this study was to identify miRNA biomarkers relating to clinicopathological features and outcome of breast cancer. A miRNA microarray analysis was performed on breast tumors of different lymph node metastasis status and with different progression signatures, indicated by overexpression of cyclin D1 and β-catenin genes, to identify miRNAs showing a significant difference in expression. The functional interaction between the candidate miRNA, miR-30a, and the target gene, Vim, which codes for vimentin, a protein involved in epithelial-mesenchymal transition, was examined using the luciferase reporter assay, western blotting, and migration and invasion assays. The association between the decreased miR-30a levels and breast cancer progression was examined in a survival analysis. miR-30a negatively regulated vimentin expression by binding to the 3'-untranslated region of Vim. Overexpression of miR-30a suppressed the migration and invasiveness phenotypes of breast cancer cell lines. Moreover, reduced tumor expression of miR-30a in breast cancer patients was associated with an unfavorable outcome, including late tumor stage, lymph node metastasis, and worse progression (mortality and recurrence) (p < 0.05). In conclusion, these findings suggest a role for miR-30a in inhibiting breast tumor invasiveness and metastasis. The finding that miR-30a downmodulates vimentin expression might provide a therapeutic target for the treatment of breast cancer.
肿瘤的复发和转移导致癌症患者预后不良。最近的研究表明,特定的 microRNAs(miRNAs)可能在癌细胞的发展中发挥重要作用。然而,miRNA 特征的预后标志物和对乳腺癌患者的结果预测尚未得到全面评估。本研究旨在确定与乳腺癌临床病理特征和结局相关的 miRNA 生物标志物。通过对具有不同淋巴结转移状态和不同进展特征(cyclin D1 和 β-catenin 基因过表达)的乳腺癌肿瘤进行 miRNA 微阵列分析,以确定表达差异显著的 miRNA。使用荧光素酶报告测定、western blot 和迁移侵袭测定来研究候选 miRNA(miR-30a)和编码波形蛋白(参与上皮-间充质转化的一种蛋白)的靶基因 Vim 之间的功能相互作用。在生存分析中检查了 miR-30a 水平降低与乳腺癌进展之间的关联。miR-30a 通过与 Vim 的 3'-UTR 结合负调控波形蛋白的表达。miR-30a 的过表达抑制了乳腺癌细胞系的迁移和侵袭表型。此外,乳腺癌患者肿瘤中 miR-30a 的表达降低与不良结局相关,包括晚期肿瘤分期、淋巴结转移和更差的进展(死亡率和复发)(p<0.05)。总之,这些发现表明 miR-30a 在抑制乳腺癌侵袭和转移中起作用。miR-30a 下调波形蛋白表达的发现可能为治疗乳腺癌提供治疗靶点。