Department of Breast Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China.
Int J Oncol. 2019 Mar;54(3):1043-1052. doi: 10.3892/ijo.2019.4671. Epub 2019 Jan 3.
Breast cancer (BC) is a common cancer and leading cause of cancer‑associated mortality in women. Abnormal expression of long non‑coding RNA FOXD2 adjacent opposite strand RNA 1 (FOXD2‑AS1) was associated with the development of a number of tumors. However, whether FOXD2‑AS1 is dysregulated in BC and its underlying mechanisms remain unclear. In the present study, it was identified that FOXD2‑AS1 expression was upregulated in BC tissue, cell lines and sphere subpopulation. Additionally, the abnormal upregulation of FOXD2‑AS1 predicted poor prognosis in patients with BC. Furthermore, downregulation of FOXD2‑AS1 decreased cell proliferation, and migratory and invasive abilities in BC cells, and decreased the growth of transplanted tumors in vivo. Downregulation of FOXD2‑AS1 decreased the percentage of CD44 antigen+/signal transducer CD24- in breast cancer stem cell (BCSC) cells, and decreased the expression of numerous stem factors, including Nanog, octamer‑binding transcription factor 4 (Oct4), and sex determining region Y‑box 2 (SOX2), and inhibited the epithelial‑mesenchymal transition process. FOXD2‑AS1 was identified to be primarily located in the cytoplasm. Using bioinformatics analysis, a reporter gene assay and reverse transcription‑polymerase chain reaction assays, it was demonstrated that microRNA (miR)‑150‑5p was able to bind directly with the 3'‑untranslated region of FOXD2‑AS1 and PFN2 mRNA. miR‑150‑5p mimics decreased the cell proliferation, migration and invasion of BC cells. FOXD2‑AS1 knockdown significantly inhibited the miR‑150‑5p inhibitor‑induced increase in Nanog, Oct4 and SOX2 expression. The miR‑150‑5p inhibitor‑induced increase in N‑cadherin, and decrease in E‑cadherin and vimentin was inhibited by FOXD2‑AS1 knockdown. Profilin 2 (PFN2) expression was significantly upregulated in BC tissues. Additionally, the abnormal upregulation of PFN2 was associated with poor prognosis in patients with BC. FOXD2‑AS1 and PFN2 expression was positively correlated. Collectively, the present results demonstrated the role of the FOXD2‑AS1/miR‑150‑5p/PFN2 axis in the development of BC, and provides novel targets for the treatment of BC, and potential biomarkers for diagnosis and prognosis of BC.
乳腺癌（BC）是一种常见的癌症，也是女性癌症相关死亡的主要原因。长链非编码 RNA FOXD2 相邻反义 strand RNA 1（FOXD2-AS1）的异常表达与许多肿瘤的发生发展有关。然而，BC 中是否存在 FOXD2-AS1 的失调及其潜在机制尚不清楚。本研究表明，BC 组织、细胞系和球体亚群中 FOXD2-AS1 的表达上调。此外，BC 患者中 FOXD2-AS1 的异常上调预示着预后不良。此外，下调 FOXD2-AS1 降低了 BC 细胞的增殖、迁移和侵袭能力，并降低了体内移植瘤的生长。下调 FOXD2-AS1 降低了乳腺癌干细胞（BCSC）细胞中 CD44 抗原+/信号转导 CD24-的比例，并降低了许多干细胞因子的表达，包括 Nanog、八聚体结合转录因子 4（Oct4）和性别决定区 Y-框 2（SOX2），并抑制了上皮-间充质转化过程。FOXD2-AS1 主要定位于细胞质中。通过生物信息学分析、报告基因检测和逆转录-聚合酶链反应检测，证明 microRNA（miR）-150-5p 能够直接与 FOXD2-AS1 和 PFN2 mRNA 的 3'-UTR 结合。miR-150-5p 模拟物降低了 BC 细胞的增殖、迁移和侵袭。FOXD2-AS1 敲低显著抑制了 miR-150-5p 抑制剂诱导的 Nanog、Oct4 和 SOX2 表达增加。FOXD2-AS1 敲低抑制了 miR-150-5p 抑制剂诱导的 N-钙黏蛋白增加和 E-钙黏蛋白和波形蛋白减少。PFN2 在 BC 组织中表达明显上调。此外，PFN2 的异常上调与 BC 患者的不良预后相关。FOXD2-AS1 和 PFN2 的表达呈正相关。综上所述，本研究结果表明 FOXD2-AS1/miR-150-5p/PFN2 轴在 BC 发展中的作用，为 BC 的治疗提供了新的靶点，并为 BC 的诊断和预后提供了潜在的生物标志物。
