93 research outputs found

    MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors

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    Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF pairs with regulation direction. Subsequently, we determined 288 and 664 dysregulated TF-miRNA-gene FFLs in SE and NSE, respectively. By constructing dysregulated FFL networks, we found that many hub nodes (12 out of 30 for SE and 8 out of 32 for NSE) in the top ranked FFLs could predict subtype-classification (Random Forest classifier, average accuracy ≄90%). These hub molecules were validated by an independent dataset. Our network analysis pinpointed several SE-specific dysregulated miRNAs (miR-200c-3p, miR-25-3p, and miR-302a-3p) and genes (EPHA2, JUN, KLF4, PLXDC2, RND3, SPI1, and TIMP3) and NSE-specific dysregulated miRNAs (miR-367-3p, miR-519d-3p, and miR-96-5p) and genes (NR2F1 and NR2F2). This study is the first systematic investigation of TF and miRNA regulation and their co-regulation in two major TGCT subtypes

    MicroRNA and Cancer

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    MicroRNAs (miRs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression and have important roles in almost all biological pathways. Deregulated miR expression has been detected in numerous cancers, where miRs act as both oncogene and tumor suppressors. Due to their important roles in tumorigenesis, miRs have been investigated as prognostic and diagnostic biomarkers and as useful targets for therapeutic intervention. From a therapeutic point of view, two modalities can serve to rectify gene networks in cancer cells. For oncomiRs, a rational means is downregulation through antagomirs. Moreover, observations of the pathological reductions in tumor-suppressive miRs have inspired the concept of “miR replacement therapy” to enhance the amount of these miRs, thereby restoring them to normal levels. However, the clinical applicability of miR-based therapies is severely limited by the lack of effective delivery systems. Therefore, to understand the role of this new class of regulators, we need to identify the mRNA targets regulated by individual miRs as well as to develop specific, efficient, and safe delivery systems for therapeutic miRs

    Involvement of EZH2-MYC loop and SALL4 in Epithelial-Mesenchymal Transition (EMT) and trastuzumab resistance process in HER2+ breast cancer

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    Breast cancer (BC) is the most common type of cancer in females worldwide. It is also the second leading cause of death in women. BC is covered with heterogeneity properties, that leads to poor prognosis and therapeutic resistance. It has always been essential to unveil the different molecular mechanisms involved in BC cancer progression, finding a suitable treatment for the patients. This thesis focuses on unwrapping the various molecular mechanisms involved in HER2+ BC subtypes, as this denotes an aggressive phenotype among other subtypes of BC. Downregulation of miR-33b has been documented in many types of cancers and involves proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, enhancer zeste homolog 2-gene (EZH2) is a master regulator of controlling the stem cell differentiation and cell proliferation processes. The implication of miR-33b in the EMT pathway and analyze the role of EZH2 in this process and interaction between them is one of the main spotlights of the thesis. miR-33b is downregulated in HER2+ BC cells vs healthy controls, where EZH2 has an opposite expression in vitro and patients’ samples. The upregulation of miR-33b suppressed proliferation, induced apoptosis, reduced invasion, migration and regulated EMT by an increase of E-cadherin and a decrease of ß-catenin and vimentin. The silencing of EZH2 mimicked the impact of miR-33b overexpression. Furthermore, the inhibition of miR-33b induces cell proliferation, invasion, migration, EMT, and EZH2 expression in non-tumorigenic cells. Notably, the Kaplan–Meier analysis showed a significant association between high miR-33b expression and better overall survival. These results suggest miR-33b as a suppressive miRNA that could inhibit tumour metastasis and invasion in HER2+ BC partly by impeding EMT through the MYC–EZH2 loop's repression. On the other hand, treatment for the HER2+ BC subtype is minimal. Trastuzumab is a monoclonal antibody, regularly used for the treatment of this specific subtype of BC. Although trastuzumab is currently considered one of the most effective oncology treatments, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. The other part of the thesis focuses on finding a novel molecular mechanism of one transcription factor (TF), Sal-like protein 4 (SALL4), a critical regulator of cancer aggressiveness and resistance treatment. HER2+ BC cells with acquired resistance to trastuzumab express a higher level of SALL4 as compared to the wild type cells. Gain and loss function experiments showed that less SALL4 expression conducted the restoration of the trastuzumab 21 | P a g e sensitivity significantly; however, the transient overexpression of SALL4 in parental cell lines induced high proliferation of the cells, resulting of the reduction of trastuzumab efficacy. Furthermore, SALL4 expression regulates the PI3K/AKT pathway, through controlling of PTEN expression. Moreover, AKT phosphorylation activated many downstream targets, such as BCL2, resulting in increased cell survival and proliferation. It has been observed that SALL4 expression regulates EMT pathway via controlling the MYC expression. SALL4 showed a physical interaction with RBBP4, a NuRD complex member, and regulates the downstream proteins such as PTEN and BCL2. This interaction also helps cells to be escaped from the trastuzumab treatment and therefore, targeting the SALL4–NuRD pathway in HER2+ BC, mostly in acquired resistance cell lines would be a promising therapeutic approach and better treatment for this specific type of cancer in future. SALL4 also predicted as a prognostic factor in all subtypes of BC through KM plotter. This study provides a viable molecular mechanism-drive therapeutic strategy for the significant subset of patients with HER2+ BC whose malignancies are driven by SALL4 expression

    Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

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    Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

    Future Aspects of Tumor Suppressor Gene

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    Tumor suppressor genes (TSGs) and their signaling networks are fast growing areas in current biomedical science. These groups of genes, which are not limited to tumor suppression, play critical roles in many cellular activities. This book, "Future Aspects of Tumor Suppressor Genes", contains some fascinating fields, from basic to translational researches, in recent TSG studies. For example, several TSG signaling pathways are addressed in this book, and both mouse and Drosophila models used for the exploration of these genes are described based on the experimental evidence. A detailed review for current knowledge of microRNA studies in the regulation of tumor growth is introduced. Additionally, how natural compounds interfere with the progression of cancer development via TSG pathways is systemically summarized. Recent progresses in cell reprogramming and stemness transition processes regulated by TSG pathways are also included in this book

    Neuronally enriched microvesicle RNAs are differentially expressed in the serums of Parkinson’s patients

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    BackgroundCirculating small RNAs (smRNAs) originate from diverse tissues and organs. Previous studies investigating smRNAs as potential biomarkers for Parkinson’s disease (PD) have yielded inconsistent results. We investigated whether smRNA profiles from neuronally-enriched serum exosomes and microvesicles are altered in PD patients and discriminate PD subjects from controls.MethodsDemographic, clinical, and serum samples were obtained from 60 PD subjects and 40 age- and sex-matched controls. Exosomes and microvesicles were extracted and isolated using a validated neuronal membrane marker (CD171). Sequencing and bioinformatics analyses were used to identify differentially expressed smRNAs in PD and control samples. SmRNAs also were tested for association with clinical metrics. Logistic regression and random forest classification models evaluated the discriminative value of the smRNAs.ResultsIn serum CD171 enriched exosomes and microvesicles, a panel of 29 smRNAs was expressed differentially between PD and controls (false discovery rate (FDR) < 0.05). Among the smRNAs, 23 were upregulated and 6 were downregulated in PD patients. Pathway analysis revealed links to cellular proliferation regulation and signaling. Least absolute shrinkage and selection operator adjusted for the multicollinearity of these smRNAs and association tests to clinical parameters via linear regression did not yield significant results. Univariate logistic regression models showed that four smRNAs achieved an AUC ≄ 0.74 to discriminate PD subjects from controls. The random forest model had an AUC of 0.942 for the 29 smRNA panel.ConclusionCD171-enriched exosomes and microvesicles contain the differential expression of smRNAs between PD and controls. Future studies are warranted to follow up on the findings and understand the scientific and clinical relevance

    miR-125 is a Novel Biomarker in Pancreatic Cancer Patients

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    Approximately 46,420 Americans are diagnosed with pancreatic cancer and 39,590 individuals die from the disease annually. Pancreatic cancer is associated with a less than 5% five-year survival rate.1 Early diagnosis is rare and surgical treatment is most beneficial before the cancer becomes locally invasive or metastatic. Previously, we identified in vitro DAMPmiRs (Damage Associated Molecular Pattern molecule induced microRNAs, miR-34c and miR-214) that are differentially expressed in peripheral blood mononuclear cells (PBMCs) upon DAMP stimulation and play an important role in regulating the inflammatory response via targeting inflammatory pathways. DAMPs are passively released into the local micro-environment, and progressively, into the systemic circulation to initiate early innate and adaptive immune responses.2,3 Whether the microRNA (miRNA) expression in pancreatic cancer patients’ PBMC is different from those of normal healthy individuals is unknown. Here, we examined the miRNA expression profile of age and sex matched samples to identify potential miRNA markers. One of the most promising markers (miR-125a-5p) was selected for further analysis in patients enrolled in our recently completed phase I/II pre-operative treatment with hydroxychloroquine and gemcitabine. We also evaluated how individual immunological stimuli affect miR-125a-5p expression in normal PBMC and validated several miR-125a-5p predicted down-stream targets

    Pathway-Based Multi-Omics Data Integration for Breast Cancer Diagnosis and Prognosis.

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    Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017
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