Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Cairo, Egypt.
Department of General Surgery, Faculty of Medicine, Cairo University, Kasr Al-Ainy, Cairo, Egypt.
J Cell Physiol. 2019 Nov;234(11):20286-20297. doi: 10.1002/jcp.28629. Epub 2019 Apr 9.
Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype. Among young females, TNBC is the leading cause of cancer-related mortalities. Recently, long noncoding RNAs (lncRNAs) are representing a promising pool of regulators for tuning the aggressiveness of several solid malignancies. However, this still needs further investigations in TNBC. The main aim of this study is to unravel the expression pattern of sONE lncRNA and its mechanistic role in TNBC. Results showed that sONE is restrictedly expressed in TNBC patients; its expression level is inversely correlated with the aggressiveness of the disease. sONE acts as a posttranscriptional regulator to endothelial nitric oxide synthase (eNOS) and thus affecting eNOS-induced nitric oxide (NO) production from TNBC cells measured by Greiss reagent. Mechanistically, sONE is a potential tumor suppressor lncRNA in TNBC cells; repressing cellular viability, proliferation, colony-forming ability, migration, and invasion capacities of MDA-MB-231. Furthermore, sONE effects were found to be extended to affect the maestro tumor suppressor TP53 and the oncogenic transcription factor c-Myc. Knocking down of sONE resulted in a marked decrease in TP53 and increase in c-Myc and consequently altering the expression status of their downstream tumor suppressor microRNAs (miRNAs) such as miR-34a, miR-15, miR-16, and let-7a. In conclusion, this study highlights sONE as a downregulated tumor suppressor lncRNA in TNBC cells acting through repressing eNOS-induced NO production, affecting TP53 and c-Myc proteins levels and finally altering the levels of a panel of tumor suppressor miRNAs downstream TP53/c-Myc proteins.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型。在年轻女性中，TNBC 是癌症相关死亡的主要原因。最近，长链非编码 RNA（lncRNA）被认为是调节几种实体恶性肿瘤侵袭性的有前途的调控因子。然而，这在 TNBC 中仍需要进一步研究。本研究的主要目的是揭示 sONE lncRNA 的表达模式及其在 TNBC 中的机制作用。结果表明，sONE 在 TNBC 患者中特异性表达；其表达水平与疾病的侵袭性呈负相关。sONE 作为内皮型一氧化氮合酶（eNOS）的转录后调节剂，从而影响 TNBC 细胞中由 Greiss 试剂测量的 eNOS 诱导的一氧化氮（NO）产生。从机制上讲，sONE 是 TNBC 细胞中的一种潜在的肿瘤抑制性 lncRNA；抑制 MDA-MB-231 细胞的细胞活力、增殖、集落形成能力、迁移和侵袭能力。此外，还发现 sONE 的作用扩展到影响主调控肿瘤抑制因子 TP53 和致癌转录因子 c-Myc。sONE 的敲低导致 TP53 明显减少，c-Myc 增加，从而改变其下游肿瘤抑制 microRNA（miRNA）的表达状态，如 miR-34a、miR-15、miR-16 和 let-7a。总之，本研究强调 sONE 是 TNBC 细胞中下调的肿瘤抑制性 lncRNA，通过抑制 eNOS 诱导的 NO 产生、影响 TP53 和 c-Myc 蛋白水平，最终改变下游 TP53/c-Myc 蛋白的一组肿瘤抑制 miRNA 的水平。
