Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Nat Rev Cancer. 2021 Jul;21(7):446-460. doi: 10.1038/s41568-021-00353-1. Epub 2021 May 5.
Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial-mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ-ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.
转移是癌症相关死亡的主要原因。它的特征是一个多步骤的过程，通过获得使癌细胞从原发性肿瘤扩散并在远处器官部位定植的分子和表型变化来发生。在过去的十年中，长非编码 RNA（lncRNA）的发现和表征揭示了它们调节作用的多样性，包括在整个转移级联中发挥的关键作用。在这里，我们回顾了 lncRNA 如何通过在离散的促转移步骤中发挥作用来促进转移，包括上皮-间充质转化、侵袭和迁移以及器官营养定植，并通过影响转移性肿瘤微环境来促进转移，通常通过与核糖核蛋白复合物相互作用或直接与其他核酸实体相互作用。我们讨论了具有体内表型的特征明确的 lncRNA，并强调了机制上的共性，例如与 TGFβ-ZEB1/ZEB2 轴或核因子-κB 途径的趋同，以及具有争议机制的 lncRNA 和方法学对机制解释的影响。此外，一些 lncRNA 可以帮助识别具有更高转移风险的肿瘤，并激发新的治疗策略，一些 lncRNA 已被证明在动物模型中作为反义寡核苷酸治疗的新靶标具有潜力。除了在转移中发挥作用的特征明确的 lncRNA 示例外，我们还讨论了 lncRNA 生物学中的争议和持续挑战。最后，我们为这个快速发展的领域提出了未来研究的领域。
