Department of Breast Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, China.
Department of Breast Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, China.
Bioorg Chem. 2021 Apr;109:104722. doi: 10.1016/j.bioorg.2021.104722. Epub 2021 Feb 10.
Breast cancer (BC) is one of the most common malignances and is a leading cause of cancer-related deaths in women globally. Triple negative breast cancer (TNBC) is a common subtype of BC. Emerging evidence has indicated the crucial roles of long noncoding RNAs (lncRNAs) in the tumorigenesis of TNBC. Our aim was to explore the role and regulatory mechanism of lncRNA HLA-F antisense RNA 1 (HLA-F-AS1) in TNBC cells. Cell counting kit-8 (CCK-8) assay, colony formation assay, flow cytometry analysis and western blot analysis were used to measure HLA-F-AS1-mediated cellular behaviors in TNBC. Xenograft tumor assay was applied to assess biological function of HLA-F-AS1 in vivo. Luciferase reporter assay and RNA pull down assay were used to verify the binding ability between molecules. Our findings demonstrated that HLA-F-AS1 expression was significantly upregulated in TNBC tissues and cells, and high level of HLA-F-AS1 indicated the poor prognosis of patients with TNBC. HLA-F-AS1 promoted TNBC progression by facilitating cell proliferation and stemness maintenance and inhibiting cell cycle arrest at G0/G1 stage and apoptosis in vitro as well as inducing tumor growth in vivo. HLA-F-AS1. In addition, signal transducer and activator of transcription 3 (STAT3) transcriptionally induced HLA-F-AS1 upregulation in TNBC cells via interacting with HLA-F-AS1 promoter. Moreover, HLA-F-AS1 acted as the molecular sponge of microRNA 541-3p (miR-541-3p) to elevate TRABD (TraB domain containing) expression in TNBC cells. Rescue experiments confirmed that the decrease of cell proliferation and stemness characteristics under silenced HLA-F-AS1 was rescued by TRABD overexpression in TNBC cells. In conclusion, STAT3-induced HLA-F-AS1 facilitates cell proliferation and stemness characteristics in TNBC by miR-541-3p-dependent upregulation of TRABD, which might provide a potential novel direction for the treatment of TNBC.
乳腺癌（BC）是最常见的恶性肿瘤之一，也是全球女性癌症相关死亡的主要原因。三阴性乳腺癌（TNBC）是 BC 的常见亚型。新出现的证据表明，长非编码 RNA（lncRNA）在 TNBC 的发生发展中起着关键作用。我们的目的是探讨 lncRNA HLA-F 反义 RNA 1（HLA-F-AS1）在 TNBC 细胞中的作用和调控机制。细胞计数试剂盒-8（CCK-8）检测、集落形成检测、流式细胞术分析和 Western blot 分析用于测量 TNBC 中 HLA-F-AS1 介导的细胞行为。异种移植肿瘤测定用于评估 HLA-F-AS1 在体内的生物学功能。荧光素酶报告基因检测和 RNA 下拉检测用于验证分子之间的结合能力。我们的研究结果表明，HLA-F-AS1 在 TNBC 组织和细胞中的表达明显上调，高水平的 HLA-F-AS1 表明 TNBC 患者的预后较差。HLA-F-AS1 在体外促进 TNBC 进展，促进细胞增殖和干细胞维持，抑制 G0/G1 期细胞周期阻滞和凋亡，并在体内诱导肿瘤生长。HLA-F-AS1 与信号转导和转录激活因子 3（STAT3）相互作用，促进 TNBC 细胞中 HLA-F-AS1 的转录诱导。此外，STAT3 通过与 HLA-F-AS1 启动子相互作用，转录诱导 HLA-F-AS1 在 TNBC 细胞中的上调。此外，HLA-F-AS1 作为 microRNA 541-3p（miR-541-3p）的分子海绵，在 TNBC 细胞中上调 TRABD 的表达。挽救实验证实，在沉默 HLA-F-AS1 的情况下，细胞增殖和干细胞特性的减少可通过 TNBC 细胞中 TRABD 的过表达得到挽救。总之，STAT3 诱导的 HLA-F-AS1 通过 miR-541-3p 依赖的 TRABD 上调促进 TNBC 中的细胞增殖和干细胞特性，这可能为 TNBC 的治疗提供一个新的潜在方向。
