Role of noncoding RNAs in diseases: DOI: 10.14800/rd.355

Most of the fundamental biological processes involve the interaction between various protein-coding and noncoding RNAs, and the RNA-binding proteins associated with them. The RNA-protein interactions results in the formation of ribonucleoprotein complexes (RNPs) and altercations in the levels and structure of either can affect the associated cellular function.  Recent studies suggest that non-protein coding share of the genome is aggressively involved in multiple functions, ranging from gene expression, chromatin modification, to cell proliferation and involved in a wide range of diseases. Further studies on the mechanisms by which ncRNAs operate would yield a wealth of information regarding their functional role and the growing understanding of RNA biology to develop new RNA-based tools for developing therapeutics

Identification of microRNAs from Atlantic salmon macrophages upon Aeromonas salmonicida infection: DOI: 10.14800/rd.303

Computational approach was used in to identify potent macrophage specific miRNAs involved in basic biological process of Salmo salar. Analysis of 1119 ESTs from macrophages of Atlantic salmon (Salmo salar) infected with Aeromonas salmonicida revealed expression of 3 miRNAs. Phylogenetic analysis of both the pre-miRNA sequence revealed its evolutionarily conserved nature among various species. Identified targets of the predicted miRNAs revealed the role of miRNA in pathogenesis, stress response and allosteric exchange of histones. Further detailed studies of these miRNAs will help in revealing its function in different biological process necessary for the action of macrophages upon pathogen infection

microRNA-135b as therapeutic target in cancers: DOI: 10.14800/rd.410

microRNAs (miRNAs) are small non-coding RNAs that can negatively regulate gene expression at the post-transcriptional level through the RNA-induced silencing complex (RISC)-mediated inhibition. Because of the imperfect and short seed-binding region of the target sequences, miRNAs hold capacity for multi-targeting and are able to regulate a wide range of cellular functions and signaling. Numerous researches have revealed that dysregulated miRNAs are closely associated with cancer progression. Moreover, genome-wide screening shows that the expression profile of miRNAs can serve as biomarkers for early diagnosis, stratifying patient outcome, and predicting treatment efficiency for cancer patients. Hence, seeking and dissecting the detailed mechanisms of cancer-associated miRNA may provide a new avenue for cancer targeting therapy. This review discussed the current proposed mechanisms of miR-135b involvement in cancer progression and tissue differentiation, both of which are considered as functional equivalents. The regulatory network of miR-135b are also addressed to further clarify the potential oncogenic role of miR-135b

Emerging role for PLC?1 MiRNA and disease: DOI: 10.14800/rd.363

Nuclear inositides are independently regulated and their regulation is totally independent from the plasma membrane counterpart, suggesting that the nucleus constitutes a functionally distinct compartment of inositol lipids metabolism. This suggests that nuclear inositol lipids themselves can modulate nuclear processes as important as transcription and pre-mRNA splicing, growth, proliferation, cell cycle regulation and differentiation. Phospholipase C ?1 (PLC?1) is a key molecule for nuclear inositide signaling. Very recently it has been highlighted that the role of PLC?1 during erythropoiesis is linked to that of miR-210. Moreover PLC?1 signaling is linked to gene regulation and changes in microRNAs (miRNAs) occurs with PLC?1 expression. Molecular targets of PLC?1 have been found to be important during myogenesis and hematopoiesis. In addition, PLC?1 signaling has been demonstrated to be impaired in diseases affecting both myogenic differentiation and affecting the hematopoietic system

miR-92a – a key player in cardiovascular remodeling: DOI: 10.14800/rd.371

  Small non-coding, highly conserved microRNAs (miRs) play a crucial role in gene regulation, especially in post-transcriptional gene silencing, and are important for vascular homeostasis as well as during pathophysiological vascular remodeling processes. miR-92a is a known negative regulator of endothelial cell proliferation, angiogenesis and vascular repair. Conversely, inhibition of miR-92a improves angiogenesis in models of hind limb- or myocardial ischemia. We recently showed that inhibition of miR-92a using specific locked nucleic acid-based antimiRs accelerates the re-endothelialization process and prevents neointimal lesion formation following wire-induced injury of murine femoral arteries. Thus, miR-92a inhibitors may represent promising therapeutic tools for the treatment of vascular diseases

Bone metastatic prostate cancer and resistance to tyrosine kinase inhibitors: an intimate relationship between loss of miR-203 and up-regulation of EGFR signaling: DOI: 10.14800/rd.345

A tumor suppressor role for miR-203 in RAS-dependent prostate cancer metastasis has been described recently by our group. We have explored the regulatory mechanisms by which miR-203 is being regulated through EGFR signaling. We investigated the molecular mechanism of metastasis and identified novel roles of genes that interact with miR-203 downstream of activated Ras. We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the EGFR ligands, AREG, EREG, and TGFA 3’UTR. Using clinical specimens and database analysis, our data suggested that decreasing miR-203 and increasing EGFR ligands, AREG, EREG, and TGFA expressions are correlated with prostate cancer progression. Since tyrosine kinase inhibitors (TKIs) have been shown to inhibit tyrosine phosphorylation of EGFR in a dose-dependent manner, we examined a role for miR-203 in TKIs-induced apoptosis in RAS-activated prostate cancer. We investigated the mechanisms by which miR-203 overexpression contributes to TKIs-resistant RAS-activated prostate cancer cells apoptosis. We have shown indications for candidate miR-203 targets that are either influenced by anti-apoptotic proteins (e.g. API5, BIRC2, and TRIAP1) or positively influenced by a novel NF-?B-inducible oncogenic molecule, TNFAIP8. These observations suggest that the latter category may be synergistically affected by the regulatory loop of miR-203 depletion and anti-apoptotic proteins overexpression. Our results provided evidence showing a role of miR-203 in regulating the expression of EGFR signaling genes in response to TKIs-resistance during prostate cancer progression

microRNA global expression analysis and genomic profiling of the camptothecin-resistant T-ALL derived cell line CPT-K5: DOI: 10.14800/rd.441

The clinical use of the camptothecin (CPT) derivatives, topotecan and irinotecan, has had a significant impact on cancer therapy. However, acquired clinical resistance to these drugs is common, which greatly hampers their clinical efficacy. MicroRNAs (miRNAs) is an exciting novel class of endogenous non-coding RNAs that negatively regulate gene expression of up to 50% of the protein-coding genes at the post-translational level. Abnormal expression of miRNAs is associated with pathogenesis of cancer and is also implicated in anticancer drug resistance phenotypes. We used global expression analysis to examine for differential miRNA expression between the camptothecin-resistant cell line CPT-K5 and its parental CPT-sensitive RPMI-8402. In the CPT-K5 cell line 18 miRNAs were deregulated. Fifteen of these were down-regulated and three were up-regulated. The miRNA-193a-3p, miR-130a-3p, and miR-29c-3p were the most down-regulated miRNAs at 205.9-fold, 33.9-fold and 5.5-fold, respectively, while the miRNA let-7i-5p was the most up-regulated at 3.9-fold. We used subtraction BAC-based array CGH analysis to examine for genomic copy number changes. Only for the three most down-regulated miRNAs a positive correlation was found with genomic loss of their chromosomal regions in which they are encoded. Potential functional targets of the differentially expressed miRNAs were examined by searching the miRBase and miRTarBase databases. Recurrent KEGG pathways that theoretically could be affected by the deregulated miRNAs are lysine degradation, cell cycle, PI3K-Akt-, ERbB- and p53- signaling pathways. We show that the intracellular levels of several miRNAs are significantly deregulated upon acquisition of CPT resistance in the T-ALL derived cell line CPT-K5, and that genomic copy number changes is not a major cause of deregulation. In addition, the most deregulated miRNAs in our study have previously been described to be involved in various types of chemotherapeutic resistance, including the chemotherapeutics CPT, gefitinib and cisplatin in other cancer and cell types. Our study adds to the current knowledge of the mechanisms of acquired CPT resistance. Specific miRNAs may prove to be future targets to reverse or inhibit development of CPT resistance thereby providing means for a more effective treatment

miR-33a, an important marker and putative therapeutic target in chronic HBV-induced fibrosis: DOI: 10.14800/rd.416

To investigate the roles and mechanisms of miR-33a in liver fibrosis, miR-33a expression in whole liver and serum samples was measured from chronic hepatitis B (CHB) patients by quantitative real-time PCR (qRT-PCR). In addition, Human and murine primary liver fibrosis-associated cells were isolated and treated with transforming growth factor-?1 (TGF-?1). We found that miR-33a expression levels in liver tissue significantly increased with a fibrosis progression manner in the human liver. Furthermore, serum miR-33a levels associated positively with progressing process of hepatic fibrosis. miR-33a was in particular increased in hepatic stellate cells (HSC) than other liver fibrosis-associated cells. Stimulation of HSCs with TGF-?1 leads to a critical increase of miR- 33a. Increasing miR-33a levels increased (whereas inhibiting miR-33a weakened) the activation role of TGF-?1 in LX-2 cells, which might be a potential mechanism through moderating Smad7 expression. Altogether, data suggest that miR-33a may be a novel marker for HSC activation and hepatic fibrosis progress, suggesting a new therapeutic target in liver fibrosis