The Role of miRNA-424 in Various Cancers: Focusing on Drug Resistance and Sensitivity

However, advanced technologies have been developed in the treatment of various cancers the mortality rate of this disease is still very high. Drug resistance is a major problem for cancer patients which causes the treatment process to fail. In addition to inhibiting drug resistance, targeted therapy is also very important in its treatment. Nowadays, miRNAs have gained increasing interest in recent years which play a major role in both drug resistance and target therapy. MicroRNA (miRNA) is an important part of non-coding RNA that regulates gene expression at a posttranscriptional level. One of these microRNAs is miR-424 that by targeting genes involved in various cellular processes can participate in proliferation, differentiation, apoptosis, invasion, angiogenesis, and drug resistance and sensitivity. In this study, we collected the role of miR-424 in a variety of cancers and by identifying the role of miR-424 in drug resistance we can reduce the effect of drug resistance in many cancers.

Comprehensive Characterization of Androgen-Responsive circRNAs in Prostate Cancer

The androgen receptor (AR) signaling pathway plays an important role in the initiation and progression of prostate cancer. Circular RNAs (circRNAs), the novel noncoding RNAs without 5′ to 3′ polarity or 3′ poly (A), play an important role in multiple diseases. However, the potential roles of androgen-responsive circRNAs in prostate cancer remain unclear. In this study, we identified 3237 androgen-responsive circRNAs and 1954 androgen-responsive mRNAs after dihydrotestosterone (DHT) stimulation using microarray. Among them, the expression of 1296 androgen-responsive circRNAs was consistent with that of their parent genes, and we thought AR might regulate the expression of these circRNAs at the transcriptional level. In addition, 1941 circRNAs expression was not consistent with their parent genes, and we speculated that AR may regulate the expression of those circRNAs at the posttranscriptional level through affecting alternative splicing. Analyzing the androgen-responsive circRNAs regulated at the posttranscriptional level, we identified two key RNA binding proteins (RBPs), WTAP and TNRC6, using the circInteractome database, which may play important role in the biogenesis of androgen-responsive circRNAs. Furthermore, we explored the potential biological functions and predicted the molecular mechanisms of two dysregulated circRNAs (circNFIA and circZNF561) in prostate cancer. In this study, we revealed that circNFIA was upregulated in prostate cancer tissues and plasma samples from patients with prostate cancer; circNFIA may play an oncogenic role in prostate cancer. In contrast, circZNF561 was downregulated and may act as a tumor suppressor in prostate cancer. Our results suggest that androgen-responsive circRNAs might regulate the progression of prostate cancer and could be novel diagnostic biomarkers.

A review of the targeting sites and biological roles of miR-4800; a novel tumor biomarker with therapeutic potential

MicroRNAs (miRNAs) are known as a group of short noncoding ribonucleic acids (ncRNAs). Mainly, they can manage gene expression at the posttranscriptional level in the essential biological and physiological functions. Significantly, more than 50% of the discovered miRNAs genes are placed in cancer‐related genomic regions, which can act as oncomiR or oncosuppressor. In this regard, growing evidence recently demonstrated the deregulation of miR-4800 in human cancers and non-cancerous diseases. However, little information is available on the biological roles of miR-4800 in cancer initiation, development, and progression. Here, we reviewed the targeting sites and biogenesis functions of the miR‐4800 family in physiological and pathological processes like human cancers, particularly with a particular focusing on the validated specific targets.

Noncoding RNAs involved in the STAT3 pathway in glioma

Glioma is the most common malignant primary brain tumour in adults. Despite improvements in neurosurgery and radiotherapy, the prognosis of glioma patients remains poor. One of the main limitations is that there are no proper clinical therapeutic targets for glioma. Therefore, it is crucial to find one or more effective targets. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of genes. Abnormal expression of STAT3 is involved in the process of cell proliferation, migration, invasion, immunosuppression, angiogenesis, dryness maintenance, and resistance to radiotherapy and chemotherapy in glioma. Therefore, STAT3 has been considered an ideal therapeutic target in glioma. Noncoding RNAs (ncRNAs) are a group of genes with limited or no protein-coding capacity that can regulate gene expression at the epigenetic, transcriptional and posttranscriptional level. In this review, we summarized the ncRNAs that are correlated with the ectopic expression of STAT3 in glioma.

Coilin enhances phosphorylation and stability of DGCR8 and promotes miRNA biogenesis

MicroRNAs (miRNAs) are ∼22 nt small noncoding RNAs that control gene expression at the posttranscriptional level through translational inhibition and destabilization of their target mRNAs. The biogenesis of miRNAs involves a series of processing steps beginning with cropping of the primary miRNA transcript by the Microprocessor complex, which is comprised of Drosha and DGCR8. Here we report a novel regulatory interaction between the Microprocessor components and coilin, the Cajal Body (CB) marker protein. Coilin knockdown causes alterations in the level of primary and mature miRNAs, let-7a and miR-34a, and their miRNA targets, HMGA2 and Notch1, respectively. We also found that coilin knockdown affects the levels of DGCR8 and Drosha in cells with (HeLa) and without (WI-38) CBs. To further explore the role of coilin in miRNA biogenesis, we conducted a series of co-immunoprecipitation experiments using coilin and DGCR8 constructs, which revealed that coilin and DGCR8 can form a complex. Additionally, our results indicate that phosphorylation of DGCR8, which has been shown to increase protein stability, is impacted by coilin knockdown. Collectively, our results implicate coilin as a member of the regulatory network governing miRNA biogenesis.

Exogenous microRNA 322-5p Reduced Neuronal Inflammation via the TRAF6/IRF5/NF-kB Axis and Restored GAD1/GABA Expression in a Pilocarpine-induced Epileptic Rat Model

Objective: MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression at the posttranscriptional level. Some dysregulated miRNAs have been shown to play essential roles in epileptic development. This study aimed to determine if microRNA-322-5p regulates seizure and seizure damage by targeting the NFκB-TLR4 associated inflammatory signaling pathway.Methods: Pilocarpine-induced epileptic rat model was established. Immunohistochemical staining demonstrated the pathology of epilepsy. The expression of microRNA-322-5p, inflammatory markers, NF-kB, TLR4, IL-1β and IL-6, and synaptic inhibitory molecules, GAD1 and GABA, were assessed by a quantitative polymerase chain reaction, and western blotting, respectively.Results: The expression of microRNA-322-5p was significantly decreased in the SE (status epilepticus) rats compared with the normal counterparts. The reduction of miR-322-5p was accompanied by an increased level of pro‑inflammatory cytokines such as IL-6 and TNF-α via increased NF-kB expression and reduced GAD1 and GABA expression. The exogenously increased miR-322-5p level by mimic molecules significantly reduced the inflammatory profiles and increased GAD1 and GABA expressions in the S.E. rat brain compared to nontreated counterparts. Conclusions: Our findings suggest that the restoration of miR-322-5p resulted in a significantly reduced TRL4/IRF1/NF-kb associated inflammatory circuit and increased GAD1 and GABA expression. These findings suggest that miR-322-5p induction may be of therapeutic potential for neural damage as a result of repeated epileptic episodes.

KRT18 Modulates Alternative Splicing of Genes Involved in Proliferation and Apoptosis Processes in Both Gastric Cancer Cells and Clinical Samples

Keratin 18 (KRT18), one of the most abundant keratins in epithelial and endothelial cells, has been reported to be aberrantly expressed in many malignancies and extensively regarded as a biomarker and important regulator in multiple cancers, including gastric cancer (GC). But the molecular regulatory mechanisms of KRT18 in GC patients and cells are largely unknown. In the present study, we analyzed the expression level of KRT18 in 450 stomach adenocarcinoma tissue samples from TCGA database and found a significantly higher expression level in tumor tissues. We then explored the potential functions of KRT18 in AGS cells (human gastric adenocarcinoma cell line) by KRT18 knockdown using siRNA and whole transcriptome RNA-seq analysis. Notably, KRT18 selectively regulates expression of cell proliferation and apoptotic genes. Beyond this, KRT18 affects the alternative splicing of genes enriched in apoptosis, cell cycle, and other cancer-related pathways, which were then validated by reverse transcription–quantitative polymerase chain reaction approach. We validated KRT18-KD promoted apoptosis and inhibited proliferation in AGS cells. We then used RNA-seq data of GC samples to further demonstrate the modulation of KRT18 on alternative splicing regulation. These results together support the conclusion that KRT18 extensively modulates diverse alternative splicing events of genes enriched in proliferation and apoptosis processes. And the dysregulated splicing factors at transcriptional or posttranscriptional level by KRT18 may contribute to the alternative splicing change of many genes, which expands the functional importance of keratins in apoptotic and cell cycle pathways at the posttranscriptional level in GC.

Selective nuclear export of mRNAs is promoted by DRBD18 in Trypanosoma brucei

Kinetoplastids, including Trypanosoma brucei, control gene expression primarily at the posttranscriptional level. Nuclear mRNA export is an important, but understudied, step in this process. The general heterodimeric export factors, Mex67/Mtr2, function in the export of mRNAs and tRNAs in T. brucei, but RNA binding proteins (RBPs) that regulate export processes by controlling the dynamics of Mex67/Mtr2 ribonucleoprotein formation or transport have not been identified. Here, we report that DRBD18, an essential and abundant T. brucei RBP, associates with Mex67/Mtr2 in vivo, likely through its direct interaction with Mtr2. DRBD18 downregulation results in partial accumulation of poly(A)+ mRNA in the nucleus, but has no effect on localization of intron-containing or mature tRNAs. Comprehensive analysis of transcriptomes from whole cell and cytosol in DRBD18 knockdown parasites demonstrates that depletion of DRBD18 leads to impairment of nuclear export of a subset of mRNAs. CLIP experiments reveal association of DRBD18 with several of these mRNAs. Moreover, DRBD18 knockdown leads to a partial accumulation of the Mex67/Mtr2 export receptors in the nucleus. Taken together, the current study supports a model in which DRBD18 regulates the selective nuclear export of mRNAs by promoting the mobilization of export competent mRNPs to the cytosol through the nuclear pore complex.

AGO2 localizes to cytokinetic protrusions in a p38-dependent manner and is needed for accurate cell division

Argonaute 2 (AGO2) is an indispensable component of the RNA-induced silencing complex, operating at the translational or posttranscriptional level. It is compartmentalized into structures such as GW- and P-bodies, stress granules and adherens junctions as well as the midbody. Here we show using immunofluorescence, image and bioinformatic analysis and cytogenetics that AGO2 also resides in membrane protrusions such as open- and close-ended tubes. The latter are cytokinetic bridges where AGO2 colocalizes at the midbody arms with cytoskeletal components such as α-Τubulin and Aurora B, and various kinases. AGO2, phosphorylated on serine 387, is located together with Dicer at the midbody ring in a manner dependent on p38 MAPK activity. We further show that AGO2 is stress sensitive and important to ensure the proper chromosome segregation and cytokinetic fidelity. We suggest that AGO2 is part of a regulatory mechanism triggered by cytokinetic stress to generate the appropriate micro-environment for local transcript homeostasis.

Bacterial chaperone protein Hfq facilitates the annealing of sponge RNAs to small regulatory RNAs

ABSTRACTBacterial small RNAs (sRNAs) in association with the chaperone protein Hfq regulate the expression of many target mRNAs. Since sRNAs’ action is crucial to engender a response to changing environmental conditions, their activity needs to be regulated. One such mechanism occurs at posttranscriptional level and involves sponge RNAs (or anti-sRNAs) which sequester sRNAs affecting their regulatory output. Both types of RNAs were identified on Hfq, but it is not known how Hfq interacts with RNA sponges and stimulates their base-pairing with sRNAs. Here, we used biochemical methods to demonstrate that anti-sRNAs resemble sRNAs by their structure and their modes of Hfq binding. Hfq facilitates sponge RNA annealing to sRNA, and each surface of the protein plays a particular role in the process. Moreover, we found that the efficiency of sponge RNA interactions with sRNAs can be improved, therefore, we propose that natural RNA sponges might not sequester sRNAs optimally.