"Sister" miRNAs in cancers.

摘要: MicroRNAs (miRNAs) are short noncoding RNAs of ~22 nucleotides that negatively regulate gene expression at the post-transcriptional level. In general, miRNAs bind to 3′ untranslated region (UTR) its target mRNA via sequence-guided specific recognition trigger degradation or translational repression. The biogenesis a miRNA enables transcribed primary (pri-miRNA) be processed by RNase II (Drosha) into precursor (pre-miRNA), which is, in turn, exported cytosol and further Dicer generate mature miRNA. Over one-third human genes thought regulated miRNAs. cancers, play highly diverse roles their influences on wide variety biological process, including cell proliferation, differentiation, signal transduction, apoptosis.1 Tissue-specific signatures temporal restrictions may alter levels miRNAs, thus they can act as either tumor suppressors oncogenes context-dependent manner.2,3 Recent studies highlight role epigenetic modulations, such DNA methylation chromatin remodeling, impacting functions tumor-initiating -suppressive genes, also contributing (1) dysregulation cancers altering production pri-miRNAs (2) impairment processing maturation. For example, aberrant promoter has been frequently observed various tumors lead reduced pri-miRNAs.4 Xhemalce et al.5 recently identified BCDIN3D, RNA methyltransferase methylate pre-miRNAs evade efficient association with thereby impair decrease overall Nonetheless, precise molecular mechanism regulation remains largely unknown. In March 22, 2013 issue Cell Death Disease, Dr Bolin Liu his colleagues6 tested whether modulation remodeling alters erbB2/erbB3 receptors, members type I receptor tyrosine kinase (RTK) family critical for breast cancer initiation progression. first time, this study revealed selective class histone deacetylase (HDAC) inhibitor (HDACi) entinostat (also known MS-275 SNDX-275) downregulated erbB2-overexpressing cells through transcription-independent manner upregulation (miR-125a, miR-125b, miR-205) have reported mRNAs. These “sister” (so called because share common targets) concert one another reduce protein, but not mRNA, inhibit downstream signaling cells. Furthermore, direct inhibition two more one, significantly attenuated entinostat-induced downregulation apoptosis cells.6 This provides novel insights regarding complexity miRNA-mediated suppression an oncogene targeted multiple could exploited therapeutic effect cancers. Development effective molecularly therapy is challenging due unpredictable responses and/or potential resistance therapy. A new generation drugs involve use mimics antagonists aim down- upregulate targets. data generated from Liu’s laboratory support utilization than order efficiently downregulate pivotal development cancers. Previously, skepticism modality might attributed off-target effects unwanted toxicities associated 100- 1000-fold. attempt improve our understanding expression, researchers postulated using 3′UTR (multiple-to-one7) opposed (multiple-to-multiple8). When examining multiple-to-one scenario, Wu al.7 analyzed combinations (miR-181c/miR-340, miR-224/miR-452) were able KRAS/MECP2 KRAS/DPYSL2, respectively. Unlike these studies, Wang al.6 provide supportive indicating (miR-125a/miR-125b/miR-205) exhibit synergistic/additive inhibitory so any single Restoration lower regulatory serve strategy combat tumorigenesis (Fig. 1). significance working sync regulation; however, issues spatial constrains docking seed sequences still poorly understood. It clear how miRNA’s binding location timing effectiveness expression. Moreover, cooperative interaction between solely predominantly modulate gene’s machinery question. Thus, basic research needed optimize experimental approach expand We believe will likely usher innovative platform robust miRNA-based therapies patients. Figure 1. Schema erbB2/erbB3. Epigenetic modulators enhance increased simultaneously 3′UTRs ...