MiRNA的研究进展

MiRNA(MicroRNA)是近年来在多种真核细胞及病毒中发现的一类内源性21-25nt短序列非编码单链RNA,在进化上具有高度的保守性,能够通过与靶mRNA特异性的碱基互补配对,引起靶mRNA的降解或者抑制其翻译,在基因调控中扮演重要的角色。本文试从MiRNA的概念特点作用机制及功能等方面对MiRNA的研究进展作一个简单回顾。     

microRNA与肿瘤的关系

miRNA是一类分布广泛的非编码小分子RNA，其长度约为22个核苷酸，它的功能是通过负调控基因的表达从而调节细胞的生理过程，但当其表达异常时可能引起疾病甚至肿瘤的形成。过去肿瘤的研究大多数都集中于对原癌基因和抑癌基因突变的研究上。目前，发现许多肿瘤的发生很可能是受miRNA的影响，miRNA也可以起到抑癌基因或原癌基因的作用。miRNA表达的异常可能与其染色体脆性位点存在几率较高有关。本文对miRNA的结构、功能及其与肿瘤发生关系等方面进行了综述。     

RNA干扰的实现及应用前景

RNA干扰现象是生物界的一种保守行为，能特异性地抑制同源基因表达，具有维持基因组稳定性和抵抗病毒人侵的作用。RNA干扰现象已在植物、真菌、低等无脊椎动物和哺乳动物等多种生物体内发现，其可能是生物界一种古老而且进化上高度保守的重要现象。RNA干扰是生物体适应外界环境、基因表达调控、抵抗外源病毒RNA侵染而保护基因组的重要机制。本文综述了RNA干扰的原理、实现方法、应用等几个方面的研究，并对RNA干扰在基因治疗上的应用前景进行了展望。     

Dicer1 functions as a haploinsufficient tumor suppressor

While the global down-regulation of microRNAs (miRNAs) is a common feature of human tumors, its genetic basis is largely undefined. To explore this question, we analyzed the consequences of conditional Dicer1 mutation (Dicer1 “floxed” or Dicer1^fl) on several mouse models of cancer. Here we show Dicer1 functions as a haploinsufficient tumor suppressor gene. Deletion of a single copy of Dicer1 in tumors from Dicer1^fl/+ animals led to reduced survival compared with controls. These tumors exhibited impaired miRNA processing but failed to lose the wild-type Dicer1 allele. Moreover, tumors from Dicer1^fl/fl animals always maintained one functional Dicer1 allele. Consistent with selection against full loss of Dicer1 expression, enforced Dicer1 deletion caused inhibition of tumorigenesis. Analysis of human cancer genome copy number data reveals frequent deletion of DICER1. Importantly, however, the gene has not been reported to undergo homozygous deletion, suggesting that DICER1 is haploinsufficient in human cancer. These findings suggest Dicer1 may be an important haploinsufficient tumor suppressor gene and, furthermore, that other factors controlling miRNA biogenesis may also function in this manner.     

Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer

Down-regulation of Drosha and Dicer has been suggested to be of prognostic value in some cancers. The aims of our study were to investigate the down-regulation of Drosha and Dicer in breast cancers and its associations with clinicopathological features, molecular subtypes and outcome. Drosha and Dicer expression was assessed with real-time RT-PCR in 245 patients with breast cancer receiving adjuvant anthracycline-based chemotherapy and compared to expression levels of normal breast tissue. Drosha down-regulation was observed in 18% of cases and was associated with high grade, high Ki-67, lack of Bcl2 expression, HER2 over-expression and gene amplification and TOPO2A gene amplification. Dicer down-regulation was found in 46% of cases and was associated with lack of expression of ER, PR and Bcl2 and with high grade, high Ki-67, triple-negative and basal-like phenotypes. Drosha and Dicer were concurrently down-regulated in 15% of cases and significantly associated with high grade and high Ki-67 index. No significant associations between down-regulation of Drosha and/or Dicer and outcome were observed. Our results suggest that down-regulation of Drosha and/or Dicer is not robustly associated with the outcome of breast cancer patients treated with adjuvant anthracycline-based chemotherapy but preferentially observed in distinct subgroups of breast cancer.