Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. Significance: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

中文翻译：

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MILIP 与 tRNA 结合促进蛋白质合成，从而驱动三阴性乳腺癌

由于缺乏有效的治疗干预分子靶点，三阴性乳腺癌（TNBC）患者预后较差。在这里，我们发现长非编码RNA（lncRNA）MILIP通过与转移RNA（tRNA）复合以促进蛋白质产生来支持TNBC细胞的存活、增殖和致瘤性，从而代表TNBC的潜在治疗靶点。 MILIP 在 TNBC 细胞中高水平表达，这些细胞通常含有肿瘤抑制因子 p53 的功能丧失突变，并且 MILIP 沉默抑制了 TNBC 细胞活力和异种移植物生长，表明 MILIP 在 TNBC 中的独特功能超出了其在抑制 p53 方面的既定作用。其他类型的癌症。机制研究表明，MILIP 与真核翻译延伸因子 1 α 1 (eEF1α1) 相互作用，并通过其可变环与 II 型 tRNA tRNALeu 和 tRNASer 形成 RNA-RNA 双链体，从而促进 eEF1α1 与这些 tRNA 的结合。破坏 MILIP 和 eEF1α1 或 tRNA 之间的相互作用会降低蛋白质合成和细胞活力。靶向MILIP抑制TNBC生长，并在体内与临床可用的蛋白质合成抑制剂奥马他辛甲琥珀酸盐协同作用。总的来说，这些结果将 MILIP 确定为一种 RNA 翻译延伸因子，可促进 TNBC 细胞中蛋白质的产生，并揭示了单独或与其他类型的蛋白质合成抑制剂联合靶向 MILIP 用于 TNBC 治疗的治疗潜力。意义：LncRNA MILIP 通过与 tRNA 和 eEF1α1 形成复合物，在支持 TNBC 蛋白质生产中发挥关键作用，从而赋予对 MILIP 靶向和蛋白质合成抑制剂组合的敏感性。