Functional roles of lncRNAs in the pathogenesis and progression of cancer.

Long noncoding RNAs (lncRNAs) act as regulators of gene expression and pivotal transcriptional regulators in cancer cells via diverse mechanisms. lncRNAs involves a variety of pathological and biological activities, such as apoptosis, cell proliferation, metastasis, and invasion. By using microarray and RNA sequencing, it was identified that dysregulation of lncRNAs affects the tumorigenesis process. Taken together, these lncRNAs are putative biomarker and therapeutic target in human malignancies. In this review, I discuss the latest finding regarding the dysregulation of some important lncRNAs and their diverse mechanisms of these lncRNAs in the pathogenesis and progression of certain cancers; also, I summarize the possible roles of lncRNAs in clinical application for diagnosis and prognosis of cancer.

A systematic review of microRNAs as potential biomarkers for diagnosis and prognosis of gastric cancer.

Gastric cancer (GC) is the third leading cause of global cancer morbidity and mortality. One of the significant challenges in GC treatment is that most GC patients are diagnosed with advanced-stage disease due to the lack of suitable biomarkers. Recent studies have shown that microRNAs (miRNAs) can acts as a potential biomarker in GC diagnosis and prognosis. I performed a systematic review of published miRNA studies in GC, which includes the miRNA expression profiles between GC tissues and normal tissues and also miRNA studies to evaluate their potential value in the diagnosis and prognosis of GC. Among the studies, upregulation of miR-21, miR-106b, miR-25, miR-214, miR-18a, miR-191, and miR-93 and downregulation of miR-375, miR-148a, miR-92, miR-155, and miR-564 were observed in GC tissues. In evaluating of diagnosis value of miRNAs, the study was performed on a combined miRNA include miR-21, miR-93, miR-106a, and miR-106b indicated the panel of these miRNAs have the highest AUC 0.887 to discriminate GC patients from healthy. Also, miR-940 with a sensitivity of 81.25% and specificity of 98.57% may be used for diagnostic biomarkers for GC. Finally, the pooled prognostic result of miR-21 for hazard ratios (HR) was 1.260 (95% CI 0.370-4.330, P < 0.001), showing that miR-21 could predict poor survival in GC patients. This systematic review can confirm that we need to find a miRNA or a panel of miRNAs with high sensitivity and specificity for further exploration to investigate a better diagnostic or therapeutic tool for personalized management of GC patients.

The significance of microRNA deregulation in colorectal cancer development and the clinical uses as a diagnostic and prognostic biomarker and therapeutic agent.

Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. Although death rates have declined over the previous decade, mainly because of enhanced screening or potential treatment alternatives, CRC remains the third leading cause of cancer-related mortality globally, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Therefore, many scientific efforts are put into the development of new diagnostic biomarkers for CRC. MicroRNAs (miRNAs), one of the epigenetics categories, have demonstrated significant roles in carcinogenesis and progression through regulating epithelial-mesenchymal transition (EMT), oncogenic signaling pathways, and metastasis. Dysregulation of miRNAs expression has been reported in many cancers, including CRC. The expression profile of miRNAs is reproducibly altered in CRC, and their expression patterns are associated with diagnosis, prognosis, and therapeutic outcomes in CRC. Recently, many studies were conducted on the dysregulation of miRNAs as a diagnostic and prognostic biomarker in CRC. Among them, some miRNAs, which include miR-21, miR-34 family, miR-155, miR-224, and miR-378, have been more studied in CRC with more prominent roles in diagnosis, prognosis, and therapy. In the present review, we summarized the latest information regarding the dysregulated miRNAs in CRC and the advantages of using miRNAs as a biomarker for CRC diagnosis, treatment, and their function in different signaling pathways involved in CRC progression. Moreover, we described the translation of miRNA research to potential therapeutic applications in the management of CRC in clinical settings.

Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression.

Gastric cancer (GC) is the second main cause of cancer-related mortality worldwide. The poor prognosis and survival of GC are due to diagnosis in an advanced, noncurable stage and with a restricted response to chemotherapy. GC is usually monitored in an advanced stage; therefore, the poor prognosis and lower level of survival rate with a restricted response to chemotherapy can be detected. Valuable and sensible biomarkers are urgently needed to display screen patients with a high risk of GC that can complement endoscopic diagnosis. Such biomarkers will enable the efficient prediction of the therapeutic response and prognosis of GC patients and prefer the establishment of an advantageous treatment method for each and every patient. Noninvasive diagnostic biomarkers may additionally make a contribution to the early identification of GC and enhance medical management. MicroRNAs (miRNAs) are a group of small noncoding RNAs that have displayed a strong association with GC. Accumulating evidence indicates that miRNAs are potential biomarkers with more than one diagnostic function for GC. Actually, miRNAs regulate cell proliferation, apoptosis, migration, invasion, and metastasis via many biological pathways through the repression of target mRNAs. The current review is accordingly to spotlight the multifaceted roles of miRNAs in GC, which would provide indications for future research. Therefore, we review right here the aberrant expression of miRNAs and underlying mechanisms, consequent effects due to miRNAs dysregulation, and accountable target genes in GC. Besides, potential clinical applications are also highlighted.

MicroRNA (miRNA)-to-miRNA Regulation of Programmed Cell Death 4 (PDCD4).

The regulation of tumor suppressor genes by microRNAs (miRNAs) is often demonstrated as a one-miRNA-to-one-target relationship. However, given the large number of miRNA sites within a 3' untranslated region (UTR), most targets likely undergo miRNA cooperation or combinatorial action. Programmed cell death 4 (PDCD4), an important tumor suppressor, prevents neoplastic events and is commonly downregulated in cancer. This study investigates the relationship between miRNA 21 (miR-21) and miR-499 in regulating PDCD4. This was explored using miRNA overexpression, mutational analysis of the PDCD4 3' UTR to assess regulation at each miRNA site, and 50% inhibitory concentration (IC50) calculations for combinatorial behavior. We demonstrate that the first miR-499 binding site within PDCD4 is inactive, but the two remaining sites are both required for PDCD4 suppression. Additionally, the binding of miR-21 to PDCD4 influenced miR-499 activity through an increase in its silencing potency and stabilization of its mature form. Furthermore, adjoining miRNA sites more than 35 nucleotides (nt) apart could potentially regulate thousands of 3' UTRs, similar to that observed between miR-21 and miR-499. The regulation of PDCD4 serves as a unique example of regulatory action by multiple miRNAs. This relationship was predicted to occur on thousands of targets and may represent a wider mode of miRNA regulation.

Efficiency of mesenchymal stem cells in treatment of urinary incontinence: a systematic review on animal models.

AIM: In recent years, the administration of stem cells has been considered a new option for treatment of urinary incontinence (UI). In the present study, the efficiency of mesenchymal stem cell (MSC) transplantation in the treatment of UI was evaluated. METHODS: Combinations of the key words 'mesenchymal stem cells', 'MSCs', 'urinary incontinence', 'urethral sphincter' and 'involuntary urination' were searched in PubMed and Science Direct databases. Following application of exclusion criteria to the 1946 papers obtained and review and duplicate articles were removed, 23 articles were considered further. The search was limited to the animal model studies. RESULTS: The data obtained from the evaluation of different studies indicated that the injected MSCs play an important role in the neovascularization and the recovery of muscle cells in UI models through the paracrine process. CONCLUSION: The obtained data suggested that further trials are needed to be focused on clinical phase of MSC therapy on the patients affected by UI.

The clinical significance of miR-335, miR-124, miR-218 and miR-484 downregulation in gastric cancer.

Gastric cancer (GC) is one of the leading types of malignancy worldwide, particularly in Asian populations. Although the exact molecular mechanism of GC development remains unknown, microRNA (miRNA) has recently been shown to be involved. The current study aims to investigate the expression levels of bioinformatically ranked miRNAs in gastric tissues. Using bioinformatics tools, we prioritized miRNAs thought to be implicated in GC. Furthermore, polyA-qPCR was used to validate bioinformatics findings in 40 GC, 31 normal gastric tissue (NG) and 45 gastric dysplasia (GD) samples. As identified by bioinformatics analysis, miR-335 was shown to be the top-ranked miRNA implicated in GC. Moreover, a significant downregulation of miR-335, miR-124, miR-218 and miR-484 was found in GC and GD compared to NG samples. We found bioinformatics to be an efficient approach to finding candidate miRNAs relevant to GC development. Finally, the findings show that downregulation of miRNAs such as miR-124 and miR-218 in gastric tissue can be a significant indicator for neoplastic transformation.

The roles of DNA epigenetics and clinical significance in Chronic Myeloid Leukemia: a review.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22) (q34;q11.2) encoding for the BCR-ABL fusion oncogene. Growing body of evidence suggests that epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukemic clone escape and disease propagation. The significant of therapeutic role in chronic myeloid leukemia (CML) depends on both genetic and epigenetic mechanisms.  This article focused on the CML and epigenetic and clinical significance. An electronic search of peer-reviewed articles was systematically performed to obtain the relevant literature with the CINAHL, cancer, Google scholar, self-experience and PubMed databases. The keywords included leukemia, cancer, illness, epigenetic. The inclusion criteria for the reviews were that the documents were original quantitative research and published in English. Articles that were not directly relevant to the present objective were excluded. Current progress in molecular biology and bioinformatics offer novel promising experiments namely as next generation sequencing for new development in epigenetic figures characterization and more understanding of the epigenetic mechanisms to be successfully utilized for personalized CML therapy in the next coming years.

Up-Regulation of miR-21, miR-25, miR-93, and miR-106b in Gastric Cancer

Background: Differential expression profile of microRNAs (miRNAs) could be a diagnosis signature for monitoring gastric cancer (GC) progression. In this study, we focus on the comparison of expression levels of miR-21, miR-25, miR-93, miR-106b, and miR-375 during the sequential pattern of GC development, including normal gastric, gastric dysplasia, and GC sample. Methods: We used SYBR Green-based quantitative-PCR to quantify miRNAs expression. Results: Our analysis revealed the increased expression levels of miR-21 (p = 0.034), miR-25 (p = 0.0003), miR-93 (p = 0.0406), and miR-106b (p = 0.023) in GC samples. In addition, GC patients with positive lymph node metastasis showed the up-regulation of miR-25, miR-93, and miR-106b (p < 0.05). Conclusion: Our findings suggested that the expression of miR-21, miR-25, miR-93, and miR-106b altered in GC, and some of them may be further investigated as biomarkers for GC early detection and prognosis prediction.

Genomic Profiling of Chronic Myelogenous Leukemia: Basic and Clinical Approach.

Chronic myeloid leukemia (CML) is a hematological stem cell cancer driven by BCR-ABL1 fusion protein. We review the previous and recent evidence on the significance of CML in diagnostic and clinic management. The technical monitoring of BCR-ABL1 with quantitative real time-PCR has been used in assessing patient outcome. The cytogenetic mark of CML is Philadelphia chromosome, that is formed by reciprocal chromosomal translocations between human chromosome 9 and 22, t(9:22) (q34:q11). It makes a BCR-ABL1 fusion protein with an anomaly tyrosine kinase activity that promotes the characteristic proliferation of progenitor cells in CML and acute lymphoblastic lymphoma. The targeting of BCR-ABL1 fusion kinase is the first novel paradigm of molecularly targeted curing.

Annexin/S100A Protein Family Regulation through p14ARF-p53 Activation: A Role in Cell Survival and Predicting Treatment Outcomes in Breast Cancer.

The annexin family and S100A associated proteins are important regulators of diverse calcium-dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.

miRTar2GO: a novel rule-based model learning method for cell line specific microRNA target prediction that integrates Ago2 CLIP-Seq and validated microRNA-target interaction data.

MicroRNAs (miRNAs) are ∼19-22 nucleotides (nt) long regulatory RNAs that regulate gene expression by recognizing and binding to complementary sequences on mRNAs. The key step in revealing the function of a miRNA, is the identification of miRNA target genes. Recent biochemical advances including PAR-CLIP and HITS-CLIP allow for improved miRNA target predictions and are widely used to validate miRNA targets. Here, we present miRTar2GO, which is a model, trained on the common rules of miRNA-target interactions, Argonaute (Ago) CLIP-Seq data and experimentally validated miRNA target interactions. miRTar2GO is designed to predict miRNA target sites using more relaxed miRNA-target binding characteristics. More importantly, miRTar2GO allows for the prediction of cell-type specific miRNA targets. We have evaluated miRTar2GO against other widely used miRNA target prediction algorithms and demonstrated that miRTar2GO produced significantly higher F1 and G scores. Target predictions, binding specifications, results of the pathway analysis and gene ontology enrichment of miRNA targets are freely available at http://www.mirtar2go.org.

A comparative analysis of lncRNAs in prostate cancer exosomes and their parental cell lines.

Prostate cancer is the second leading cancer in men world-wide. Due to its heterogeneous nature, a considerable amount of research effort has been dedicated in identifying effective clinical biomarkers with a focus on proteins, messenger RNA and microRNAs [1]. However, there is limited data on the role and expression of long noncoding RNAs (lncRNAs) in prostate cancer exosomes [2]. This array dataset which is linked to our publication describes the profiling of human lncRNAs in prostate cancer and their exosomes from five different cell lines [3]. From this dataset, we identified a list of statistically significant prostate cancer lncRNAs which are differentially expressed in the exosomes compared to their parent cell lines. This dataset has been deposited into Gene Expression Omnibus (GSE81034).

Expression of microRNAs in HPV negative tonsil cancers and their regulation of PDCD4.

Global rates of tonsil cancer have been increasing since the turn of the millennia, however we still have a limited understanding of the genes and pathways which control this disease. This array dataset which is linked to our publication (Zhang et al., 2015) describes the profiling of human miRNAs in tonsil and normal adjacent tissues. With this dataset, we identified a list of microRNA (miRNA) which were highly over represented in tonsil cancers and showed that several miRNAs were able to regulate the tumour suppressor PDCD4 in a temporal manner. The dataset has been deposited into Gene Expression Omnibus (GSE75630).

Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes.

Long non-coding RNAs (lncRNAs) form the largest transcript class in the human transcriptome. These lncRNA are expressed not only in the cells, but they are also present in the cell-derived extracellular vesicles such as exosomes. The function of these lncRNAs in cancer biology is not entirely clear, but they appear to be modulators of gene expression. In this study, we characterize the expression of lncRNAs in several prostate cancer exosomes and their parental cell lines. We show that certain lncRNAs are enriched in cancer exosomes with the overall expression signatures varying across cell lines. These exosomal lncRNAs are themselves enriched for miRNA seeds with a preference for let-7 family members as well as miR-17, miR-18a, miR-20a, miR-93 and miR-106b. The enrichment of miRNA seed regions in exosomal lncRNAs is matched with a concomitant high expression of the same miRNA. In addition, the exosomal lncRNAs also showed an over representation of RNA binding protein binding motifs. The two most common motifs belonged to ELAVL1 and RBMX. Given the enrichment of miRNA and RBP sites on exosomal lncRNAs, their interplay may suggest a possible function in prostate cancer carcinogenesis.

RNA Binding Proteins in the miRNA Pathway.

microRNAs (miRNAs) are short ~22 nucleotides (nt) ribonucleic acids which post-transcriptionally regulate gene expression. miRNAs are key regulators of all cellular processes, and the correct expression of miRNAs in an organism is crucial for proper development and cellular function. As a result, the miRNA biogenesis pathway is highly regulated. In this review, we outline the basic steps of miRNA biogenesis and miRNA mediated gene regulation focusing on the role of RNA binding proteins (RBPs). We also describe multiple mechanisms that regulate the canonical miRNA pathway, which depends on a wide range of RBPs. Moreover, we hypothesise that the interaction between miRNA regulation and RBPs is potentially more widespread based on the analysis of available high-throughput datasets.