癌症中的miRNA-lncRNA交叉调节景观：从分子机制到治疗和诊断应用

摘要(中文译文)

在过去二十年中，非编码RNA（ncRNAs）已成为基因表达的关键调控因子，重塑了基因组主要以蛋白质编码为主的经典观点。其中，微小RNA（miRNAs）和长链非编码RNA（lncRNAs）在多个层面控制基因表达中发挥核心作用。这些分子并非独立发挥作用，而是形成复杂且相互关联的调控网络，其相互作用在癌症中显得尤为重要。本综述旨在探讨miRNA-lncRNA交叉调控的机制，并探索其在肿瘤生物学中的功能和临床意义。我们对当前文献进行了全面分析，重点关注研究癌症中miRNA-lncRNA相互作用的研究。特别关注机制方面的见解，包括竞争性内源RNA（ceRNA）假说，以及涉及直接RNA相互作用和染色质相关过程的替代调控模型。miRNA-lncRNA相互作用与不同肿瘤类型的癌症进展和治疗反应相关，尽管其机制高度依赖于具体情境。虽然基于竞争共享微小RNA响应元件（MREs）的ceRNA假说提供了有用的框架，但它并不能完全解释所有观察到的现象。证据表明，miRNAs可以直接调控lncRNA的稳定性，而lncRNAs可以影响miRNA的生物发生。此外，染色质相关机制表明这些相互作用超越了转录后调控。这些RNA网络与主要致癌通路交叉，包括PI3K/AKT/mTOR信号传导、缺氧反应以及表观遗传调控因子如EZH2，从而影响增殖、上皮-间质转化（EMT）和代谢重编程等关键癌症过程。从临床角度来看，ncRNAs在生物体液中的稳定性凸显了其作为生物标志物的潜力。与单一标志物相比，联合miRNA-lncRNA特征可能提高诊断和预后准确性，但仍需进一步验证。靶向ncRNA网络的治疗策略，如miRNA模拟物、antagomiRs和lncRNA导向方法，正在研究中；然而，与递送、特异性和毒性相关的挑战仍然存在。miRNA-lncRNA交叉调控代表了癌症中基因调控的一个复杂且多层面的层次。对这些相互作用的更深入理解可以支持开发更准确的诊断工具和更有效的基于RNA的治疗策略，尽管仍需要解决重大的技术和生物学挑战。

Abstract

Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression at multiple levels. Rather than acting independently, these molecules form complex and interconnected regulatory networks, and their interplay appears particularly relevant in cancer. This review aims to examine the mechanisms underlying miRNA-lncRNA cross-regulation and to explore their functional and clinical implications in tumor biology. We performed a comprehensive analysis of the current literature focusing on studies investigating miRNA-lncRNA interactions in cancer. Particular attention was given to mechanistic insights, including the competing endogenous RNA (ceRNA) hypothesis, as well as alternative regulatory models involving direct RNA interactions and chromatin-associated processes. miRNA-lncRNA interactions have been associated with cancer progression and therapeutic response across different tumor types, although their mechanisms are highly context-dependent. While the ceRNA hypothesis, based on competition for shared microRNA response elements (MREs), provides a useful framework, it does not fully explain all observed phenomena. Evidence shows that miRNAs can directly regulate lncRNA stability, whereas lncRNAs can influence miRNA biogenesis. Additionally, chromatin-related mechanisms suggest that these interactions extend beyond post-transcriptional regulation. These RNA networks intersect with major oncogenic pathways, including PI3K/AKT/mTOR signaling, hypoxia responses, and epigenetic regulators such as EZH2, thereby affecting key cancer processes such as proliferation, epithelial-mesenchymal transition (EMT), and metabolic reprogramming. From a clinical perspective, the stability of ncRNAs in biological fluids highlights their potential as biomarkers. Combined miRNA-lncRNA signatures may improve diagnostic and prognostic accuracy compared to single markers, although further validation is required. Therapeutic strategies targeting ncRNA networks, such as miRNA mimics, antagomiRs, and lncRNA-directed approaches, are under investigation; however, challenges related to delivery, specificity, and toxicity remain. miRNA-lncRNA cross-regulation represents a complex and multifaceted layer of gene regulation in cancer. A deeper understanding of these interactions could support the development of more accurate diagnostic tools and more effective RNA-based therapeutic strategies, although significant technical and biological challenges still need to be addressed.

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