Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Cancer J. 2012 May-Jun;18(3):232-7. doi: 10.1097/PPO.0b013e318258b75b.
It has long been established that cancers can become addicted to particular oncogenes. Despite the genetic complexity that governs tumorigenesis, certain cancers can exhibit a critical dependency on the expression of a single oncogene, which when removed leads to death of the cancer cell. Recent observations on the relationships between regulatory RNAs and cancer have revealed that this concept of oncogene addiction extends to microRNAs (miRNAs) as well. Certain cancers exhibit a dependency on the expression of a single oncogenic miRNA, or oncomiR. The field of miRNA biology and its involvement in diseases such as cancer have seen tremendous advances over the past decade. However, little is known about the phenomenon of oncomiR addiction. In this review, we introduce the concept of proto-oncomiRs, or miRNAs that gain oncogenic activity after an initiating event. Furthermore, by highlighting the role of proto-oncomiRs in generating malignant phenotypes, we glean possible insights into the mechanisms that guide oncomiR addiction. In addition, toward the realization of genetically driven personalized medicine, some of the most clinically successful anticancer strategies have involved targeting addictive oncogenes such as HER2, BCR/ABL, EGFR, and VEGF. Elucidating how addictive miRNAs can perpetuate cancer may reveal additional critical molecular targets to exploit for therapeutic purposes. Therefore, in this review, we also summarize the field of anti-miRNA therapeutics, in which antisense and nanoscale delivery technologies are the driving force. Addictive oncomiRs are a double-edged sword; addicted cancers are dependent on oncomiRs that are highly potent therapeutic targets. Dissection of this phenomenon may reveal the mechanisms through which lynchpin miRNAs can perpetuate cancer and present a new paradigm for miRNA-based cancer therapy.
长期以来，人们已经认识到癌症可能会对特定的癌基因产生依赖。尽管控制肿瘤发生的遗传复杂性，但某些癌症可能表现出对单个癌基因表达的关键依赖性，当去除该基因时会导致癌细胞死亡。最近关于调控 RNA 与癌症之间关系的观察结果表明，这种癌基因成瘾的概念也扩展到了 microRNAs（miRNAs）。某些癌症表现出对单个致癌 miRNA 或 oncomiR 的表达的依赖性。过去十年中，miRNA 生物学及其在癌症等疾病中的作用领域取得了巨大进展。然而，关于 oncomiR 成瘾的现象知之甚少。在这篇综述中，我们介绍了原癌 miRNA 的概念，即在起始事件后获得致癌活性的 miRNA。此外，通过强调原癌 miRNA 在产生恶性表型中的作用，我们可以深入了解指导 oncomiR 成瘾的机制。此外，为了实现基于遗传的个性化医学，一些最成功的临床抗癌策略涉及靶向成瘾性癌基因，如 HER2、BCR/ABL、EGFR 和 VEGF。阐明成瘾性 miRNA 如何持续癌症可能会揭示更多用于治疗目的的关键分子靶标。因此，在这篇综述中，我们还总结了抗 miRNA 治疗学领域，其中反义寡核苷酸和纳米级递药技术是驱动力。成瘾性 oncomiR 是一把双刃剑；成瘾性癌症依赖于高度有效的治疗靶点 oncomiR。对这种现象的剖析可能揭示了关键 miRNA 持续癌症的机制，并为基于 miRNA 的癌症治疗提供了新的范例。
