文章：

MicroRNAs在通往临床的路上：验证和靶向MicroRNAs用于癌症治疗的进展

MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy

原文发布日期：2011-11-24

DOI: 10.1038/nrc3166

类型: Review Article

开放获取: 否

要点：

1. Recently generated germline transgenic and knockout mice have provided a detailed view of the implication of the gain or loss of individual microRNAs (miRNAs), miRNA clusters and the miRNA processing machinery in cancer. These have been classified as oncogenic (such as miR-155, miR-21 and miR-17∼92), tumour-suppressive (such as miR-15∼16, LIN28, DICER) or context-dependent (such as miR-146 and miR-29).
2. miRNAs and the miRNA processing machinery are involved in all stages of metastatic disease. Some — such as miR-200, the LIN28–let-7 interaction and DICER — contribute to both metastasis and primary tumour development, whereas others, such as miR-31 and miR-10b, are unique to metastasis.
3. Studies uncovering miRNA function have led to their therapeutic application. Delivering tumour-suppressive miRNAs and silencing oncogenic miRNAs with antagomirs has been successful in various mouse models. Many of these studies began with overexpression and knockdown strategies and have since progressed to delivering miRNA-based molecules intranasally, intratumorally or systemically.
4. Expanding on their therapeutic application, miRNAs are also being evaluated for their ability to sensitize cancers to chemotherapeutics. Much of this work is being accomplished in cell culture, with the hope that it will soon transition into preclinical model systems.

要点翻译：

1. 近期建立的生殖系转基因与基因敲除小鼠模型，为揭示单个microRNA（miRNA）、miRNA簇及miRNA加工机制在癌症中功能获得或丧失的意义提供了精细视角。这些分子已被归类为致癌性（如miR-155、miR-21和miR-17∼92）、肿瘤抑制性（如miR-15∼16、LIN28、DICER）或环境依赖性（如miR-146和miR-29）。
2. miRNA及其加工机制参与转移性疾病的所有阶段。其中部分分子——如miR-200、LIN28–let-7相互作用体和DICER——同时影响转移与原发肿瘤发展，而其他分子（如miR-31和miR-10b）则特异性作用于转移过程。
3. 对miRNA功能的深入研究推动了其治疗应用。通过递送肿瘤抑制性miRNA及使用antagomirs沉默致癌miRNA，已在多种小鼠模型中取得成效。这些研究最初采用过表达和敲低策略，现已发展为经鼻内、瘤内或全身途径递送基于miRNA的分子。
4. 基于治疗应用的拓展，miRNAs正被评估其增强癌症化疗敏感性的能力。目前大部分工作通过细胞培养完成，预计将很快过渡到临床前模型系统进行研究。

英文摘要：

In normal cells multiple microRNAs (miRNAs) converge to maintain a proper balance of various processes, including proliferation, differentiation and cell death. miRNA dysregulation can have profound cellular consequences, especially because individual miRNAs can bind to and regulate multiple mRNAs. In cancer, the loss of tumour-suppressive miRNAs enhances the expression of target oncogenes, whereas increased expression of oncogenic miRNAs (known as oncomirs) can repress target tumour suppressor genes. This realization has resulted in a quest to understand the pathways that are regulated by these miRNAs using in vivo model systems, and to comprehend the feasibility of targeting oncogenic miRNAs and restoring tumour-suppressive miRNAs for cancer therapy. Here we discuss progress in using mouse models to understand the roles of miRNAs in cancer and the potential for manipulating miRNAs for cancer therapy as these molecules make their way towards clinical trials.

摘要翻译： 

在正常细胞中，多种微小RNA（miRNA）共同作用，维持包括增殖、分化和细胞死亡在内的多种过程的平衡。miRNA失调可能对细胞产生深远影响，尤其是因为单个miRNA可以结合并调控多个mRNA。在癌症中，抑癌性miRNA的缺失会增强靶癌基因的表达，而癌性miRNA（即oncomir）表达的增加则可抑制靶抑癌基因。这一认识促使人们利用体内模型系统探究这些miRNA所调控的信号通路，并评估靶向癌性miRNA及恢复抑癌性miRNA用于癌症治疗的可行性。在此，我们回顾利用小鼠模型解析miRNA在癌症中作用的研究进展，并探讨随着这些分子走向临床试验，操控miRNA用于癌症治疗的潜力。

原文链接：

MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy