C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, we report a c-Myc pathway-targeted screening of seven natural anticancer compounds, in which we identified cryptotanshinone as a highly promising agent for CML therapy. Cryptotanshinone depletes c-Myc in CML by repressing the phosphorylation of STAT5.Decreased viability of K562 cells correlated with p-STAT5 suppression. Unexpectedly, imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells. We demonstrated that cryptotanshinone, as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BCR-ABL kinase-independent drug resistance. Moreover, we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance(MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR. Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR. These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in CML cells by targeting p-STAT5 and p-STAT3, providing a new strategy for CML therapy that takes advantage of natural products.
MicroRNAs（miRNAs） are a class of endogenous small non-coding RNAs that modulate diverse biological processes predominantly by translation inhibition or induction of mRNA degradation.They are important regulatory elements involved in renal physiology and pathology.Dysregulation of miRNAs disrupts early kidney development,renal progenitor cell differentiation and the maintenance of mature nephrons.miRNAs are also reported to participate in various renal diseases,including chronic kidney disease,acute kidney injury, allograft acute rejection and renal cell carcinoma.Differentially regulated miRNAs may represent innovative biomarkers for diagnosis and prognosis.Therefore,determining the roles of miRNAs in different types of renal diseases will help to clarify the pathogenesis and facilitate the development of novel therapies.
The pervasive transcription of the genome creates many types of non-coding RNAs(nc RNAs).However,we know very little regarding the functions and the regulatory mechanisms of these nc RNAs.Exploring the interactions of RNA and RNA binding proteins(RBPs) is vital because it can allow us to truly understand how these nc RNAs behave in vivo.High-throughput sequencing of RNA isolated by cross-linking immunoprecipitation(HITS-CLIP or CLIP-seq) and its variants have been successfully used as systemic techniques to study RBP binding sites.In this review,we will explain the major differences between the CLIP techniques,summarize successful applications of these techniques,discuss limitations of CLIP,present some suggested solutions and project their promising future roles in studying the RNA world.
microRNAs （miRNAs） constitute a unique class of endogenous small non-coding RNAs that regulate gene expression post-transcriptionally. Studies over the past decade have uncovered a r^curring paradigm in which miRNAs are key regulators of cellular behavior under various physiological and pathological conditions. Most surprising is the recent observation that miRNAs have emerged as competent players in somatic cell reprogramming, suggesting an especially significant role for these small RNAs in cell fate settings. Here, we discuss the possible mechanisms underlying miRNA-mediated cell programming （i.e., the development and differentiation of embryonic stem cells） and reprogramming （i.e., turning somatic cells into pluripo- tent stem cells or other lineages）, and provide a ＂Helm＂ model of miRNAs in cell fate decision and conversion.
