Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Cell Death Dis. 2019 Mar 20;10(4):270. doi: 10.1038/s41419-019-1513-5.
Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer with the absence of targeted therapy, resulting in poor prognosis in patients. Chemotherapy remains the mainstay of treatment for TNBC; however, development of drug resistance is the main obstacle for successful treatments. In recent years, long non-coding RNA (lncRNA) has been implicated in multiple biological functions in various diseases, particularly cancers. Accumulating evidence suggested that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression is dysregulated in many human cancers and thus is a useful prognostic marker for cancer patients. Nevertheless, the mechanism of how NEAT1 confers drug resistance in TNBC is still largely unknown. We performed lncRNA profiling by the LncRNA Profiler qPCR Array Kit in normal control (NC) and breast cancers (BC) blood samples and further validated in a larger cohort of samples by qRT-PCR. Gene expression level and localization were investigated by qRT-PCR, western blotting, and immunofluorescence staining. Flow cytometric analysis was carried out to detect cancer stem cells. Functional studies were performed both in vitro and in vivo xenograft model. Among 90 lncRNAs, NEAT1 was highly expressed in the blood samples of breast cancer patients than in NC. In particular, the expression of NEAT1 was higher in TNBC tissues than other subgroups. Functional studies revealed that NEAT1 conferred oncogenic role by regulating apoptosis and cell cycle progression in TNBC cells. We identified that knockdown of NEAT1 sensitized cells to chemotherapy, indicating the involvement in chemoresistance. Importantly, shNEAT1 reduced stem cell populations such as CD44+/CD24-, ALDH+, and SOX2+, implicating that NEAT1 was closely related to cancer stemness in TNBC. Our data highlighted the roles of NEAT1 chemoresistance and cancer stemness, suggesting that it could be used as a new clinical therapeutic target for treating TNBC patients especially those with drug resistance.
三阴性乳腺癌（TNBC）是一种缺乏靶向治疗的恶性乳腺癌亚型，导致患者预后不良。化疗仍然是 TNBC 的主要治疗方法；然而，耐药性的发展是成功治疗的主要障碍。近年来，长链非编码 RNA（lncRNA）在各种疾病中，尤其是癌症中，参与了多种生物学功能。越来越多的证据表明，lncRNA 核斑浆组装转录本 1（NEAT1）在许多人类癌症中的表达失调，因此是癌症患者的有用预后标志物。然而，NEAT1 如何在 TNBC 中赋予耐药性的机制在很大程度上仍然未知。我们通过 LncRNA Profiler qPCR 阵列试剂盒对正常对照（NC）和乳腺癌（BC）血液样本进行了 lncRNA 谱分析，并通过 qRT-PCR 在更大的样本队列中进一步验证。通过 qRT-PCR、western blot 和免疫荧光染色研究基因表达水平和定位。通过流式细胞术分析检测癌症干细胞。在体外和体内异种移植模型中进行了功能研究。在 90 个 lncRNA 中，NEAT1 在乳腺癌患者的血液样本中表达高于 NC。特别是，NEAT1 在 TNBC 组织中的表达高于其他亚组。功能研究表明，NEAT1 通过调节 TNBC 细胞的凋亡和细胞周期进程发挥致癌作用。我们发现，下调 NEAT1 可使细胞对化疗敏感，表明其参与了耐药性。重要的是，shNEAT1 减少了 CD44+/CD24-、ALDH+和 SOX2+等干细胞群体，表明 NEAT1 与 TNBC 的癌症干性密切相关。我们的数据强调了 NEAT1 耐药性和癌症干性的作用，表明它可作为治疗 TNBC 患者特别是耐药患者的新临床治疗靶点。
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