Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Exp Cell Res. 2020 Nov 15;396(2):112331. doi: 10.1016/j.yexcr.2020.112331. Epub 2020 Oct 13.
Triple negative breast cancer (TNBC) is a subtype of breast cancer with poorest survival outcome and is prone to metastasis. TUFT1 and the long non-coding RNA (lncRNA), DANCR, play vital roles in metastasis and progression of various cancers. However, the correlation between TUFT1 and DANCR in TNBC and their downstream molecular mechanisms are still undetermined. We demonstrated that upregulation of TUFT1 in TNBC was related to a worse survival in TNBC patients. The TNBC cells invasiveness was augmented by TUFT1 in a dose-dependent manner, while inhibiting TUFT1 repressed the invasiveness. Particularly, the expression of TUFT1 was positively correlated with the expression of DANCR in TNBC tissues. In addition, TUFT1 increased DANCR expression, while silencing DANCR ameliorated the invasiveness of TNBC cells induced by TUFT1. As demonstrated, TUFT1 interacted with miR-874-3p. Subsequently, qRT-PCR together with luciferase reporter further demonstrated that DANCR acted as competing endogenous (ceRNA) for miR-874-3p, thereby regulating the de-repression of SOX2 and advancing epithelial-mesenchymal transition (EMT) in TNBC. The present research shows that TUFT1 promotes the malignant development in TNBC via enhancing the expression of DANCR. The upregulation of DANCR may contribute to the progression and tumor invasiveness of TNBC, considering that DANCR functions as a miR-874-3p sponge, thus modulating SOX2 positively. Collectively, the present study explored the molecular mechanism underlying TUFT1 in TNBC, raising a TUFT1-mediated therapy for the treatment of patients with TNBC.
三阴性乳腺癌（TNBC）是一种生存预后最差且易发生转移的乳腺癌亚型。TUFT1 和长链非编码 RNA（lncRNA）DANCR 在各种癌症的转移和进展中发挥着重要作用。然而，TUFT1 和 DANCR 在 TNBC 中的相关性及其下游分子机制尚不清楚。我们证明，TNBC 中 TUFT1 的上调与 TNBC 患者的生存预后较差有关。TNBC 细胞的侵袭性随 TUFT1 浓度的增加呈剂量依赖性增强，而抑制 TUFT1 则抑制了侵袭性。特别是，TUFT1 的表达与 TNBC 组织中 DANCR 的表达呈正相关。此外，TUFT1 增加了 DANCR 的表达，而沉默 DANCR 则改善了 TUFT1 诱导的 TNBC 细胞的侵袭性。研究表明，TUFT1 与 miR-874-3p 相互作用。随后，qRT-PCR 结合荧光素酶报告实验进一步表明，DANCR 作为 miR-874-3p 的竞争性内源性 RNA（ceRNA），从而调节 SOX2 的去抑制作用，促进 TNBC 中的上皮-间充质转化（EMT）。本研究表明，TUFT1 通过增强 DANCR 的表达促进 TNBC 的恶性发展。考虑到 DANCR 作为 miR-874-3p 的海绵，正向调节 SOX2，因此上调 DANCR 可能有助于 TNBC 的进展和肿瘤侵袭性。综上所述，本研究探讨了 TUFT1 在 TNBC 中的分子机制，为 TNBC 患者的治疗提供了一种 TUFT1 介导的治疗方法。
