188 research outputs found

    Transcription regulation and candidate diagnostic markers of esophageal cancer

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    Philosophiae Doctor - PhDEsophageal cancer (EC) ranks among the ten most frequent cancers worldwide. Mortality rates associated with EC are very similar to the incidence rates due to the relatively late stage of diagnosis and the poor efficacy of treatment. The aim of this study was to enhance our insights of putative transcriptional circuitry of EC genes, thereby potentially positively impacting our knowledge of therapeutic targets, providing indications as to more appropriate lines of treatment, and additionally allowing for the determination of putative candidate diagnostic markers for the early stage detection of EC. This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer. DDEC contains known and novel information for 529 differentially expressed EC genes compiled using scientific publications from PubMed and is freely accessible for academic and non-profit users at http://apps.sanbi.ac.za/ddec/. The novel information provided to users of the DDEC is the lists of putative transcription factors that potentially control the 529 manually curated genes. The value of the information accessible through the database was further refined by providing precompiled text-mined and data-mined reports about each of these genes to allow for easy exploration of information about associations of EC-implicated genes with other human genes and proteins, metabolites and enzymes, toxins, chemicals with pharmacological effects, disease concepts and human anatomy. This feature has the capacity to display potential associations that are rarely reported and thus difficult to identify, and it enables the inspection of potentially new ‘association hypotheses’ generated based on the precompiled reports. This study further illustrates how the biocurated esophageal squamous cell carcinoma (ESCC) genes in the database may represent a reliable starting point for exploring beyond current knowledge of the transcriptional circuitry of estrogen related hormone therapy. The genes were used to develop a method that identified 44 combinations of transcription factors (TFs) that characterize the promoter sequence of estrogen responsive genes implicated in ESCC. These significantly over-represented combinations of TFs were then used to increase confidence in the 47 novel putative estrogen response genes that may be related to ESCC too. Coincidently, two of the novel putative estrogen response genes were verified by current (2009), experimental publications.South Afric

    Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

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    Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer

    Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer

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    Cancer remains one of the major cause of death in the Western world. Although, it has been demonstrated that new therapies can improve the outcome of cancer patients, still many patients relapse after treatment. Therefore, there is a need to identify novel factors involved in cancer development and/or progression. Recently, neutrophil gelatinase-associated lipocalin (NGAL) has been suggested as a key player in different cancer types. Its oncogenic effect may be related to the complex NGAL/MMP-9. In the present study, NGAL was analyzed at both transcript and protein levels in different cancer types by analysing 38 public available microarray datasets and the Human Protein Atlas tool. NGAL transcripts were significantly higher in the majority of solid tumors compared to the relative normal tissues for every dataset analyzed. Furthermore, concordance of NGAL at both mRNA and protein levels was observed for 6 cancer types including bladder, colorectal, liver, lung, ovarian, and pancreatic. All metastatic tumors showed a decrease of NGAL expression when compared to matched primary lesions. According to these results, NGAL is a candidate marker for tumor growth in a fraction of solid tumors. Further investigations are required to elucidate the function of NGAL in tumor development and metastatic processes

    Identification of Molecular Mechanisms Underlying the Development of Barrett\u27s Esophagus

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    Esophageal cancer is one of the deadliest cancers in the U.S and worldwide. Esophageal cancer is characterized by two subtypes: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). One of the major risk factors for the development of EAC is Barrett\u27s esophagus (BE). BE is defined as incomplete intestinal metaplasia characterized by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. Currently, the cell of origin for human BE has yet to identified. Using an innovative 3D organotypic culture system, we explored the role of inhibition of Notch signaling promotion of transdifferentiation of esophageal epithelial cells to BE. Our RNA microarray and tissue microarray (TMA) data support the premise that loss of Notch signaling is involved in BE. Inhibition of Notch signaling by dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression, promoted transdifferentiation of esophageal epithelial cells towards BE as demonstrated by increased expression of columnar keratins and glandular mucins with decreased expression of squamous keratins. Our data show KLF4 and HATH1, as downstream effectors of the inhibition of Notch signaling, are involved in the initiation of BE. We investigated whether these findings translated into a genetically engineered mouse model. We addressed this by engineering transgenic mice to conditionally overexpress MYC specifically in the esophageal epithelium with the EBV-L2 (L2) promoter. We used a Tet-ON system to conditionally express MYC. To achieve this we created two new transgenic mice: TetOp-Myc and L2-rtTA;TetOp-CreERT2. We bred L2-rTta; TetOp-Myc mice with K14-Cdx2 and TetOp-dnMAML mice, in order to replicate our in vivo studies. These studies are ongoing. Invasion is a theme common to BE/EAC and ESCC. As a separate consideration, we investigated the mechanisms underlying invasion in ESCC. Using esophageal epithelial cells transformed by overexpression of EGFR and p53R175H, we found a novel link between p53R175H and c-Met, a receptor tyrosine kinase. These transformed cells show increased expression of the c-Met receptor mediated by p53R175H overexpression. We show inhibition of c-Met expression in the transformed cells (EPC-hTERT-EGFR-p53R175H) diminishes invasion. Our data suggest a new avenue of therapeutics for ESCC through the use of c-Met inhibitors

    SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

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    SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment

    Single-cell mapping of N6-methyladenosine in esophageal squamous cell carcinoma and exploration of the risk model for immune infiltration

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    BackgroundN6-methyladenosine (m6A) modification is the most common RNA modification, but its potential role in the development of esophageal cancer and its specific mechanisms still need to be further investigated.MethodsBulk RNA-seq of 174 patients with esophageal squamous carcinoma from the TCGA-ESCC cohort, GSE53625, and single-cell sequencing data from patients with esophageal squamous carcinoma from GSE188900 were included in this study. Single-cell analysis of scRNA-seq data from GSE188900 of 4 esophageal squamous carcinoma samples and calculation of PROGENy scores. Demonstrate the scoring of tumor-associated pathways for different cell populations. Cell Chat was calculated for cell populations. thereafter, m6A-related differential genes were sought and risk models were constructed to analyze the relevant biological functions and impact pathways of potential m6A genes and their impact on immune infiltration and tumor treatment sensitivity in ESCC was investigated.ResultsBy umap downscaling analysis, ESCC single-cell data were labelled into clusters of seven immune cell classes. Cellchat analysis showed that the network interactions of four signaling pathways, MIF, AFF, FN1 and CD99, all showed different cell type interactions. The prognostic risk model constructed by screening for m6A-related differential genes was of significant value in the prognostic stratification of ESCC patients and had a significant impact on immune infiltration and chemotherapy sensitivity in ESCC patients.ConclusionIn our study, we explored a blueprint for the distribution of single cells in ESCC based on m6A methylation and constructed a risk model for immune infiltration analysis and tumor efficacy stratification in ESCC on this basis. This may provide important potential guidance for revealing the role of m6A in immune escape and treatment resistance in esophageal cancer

    Therapeutic potential of Rad51 inhibition

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    DNA provides the instructions and regulation of cell growth and survival. Mutations in DNA can cause uncontrolled and unregulated cell proliferation, resulting in cancer. Treatment of cancer involves physical removal of these cells through surgery or inducing cell death by causing irreversible damage to DNA through chemotherapy and radiotherapy. However, natural DNA repair mechanisms may interfere with therapy and may even be increased in cases of therapy resistant cancer. The use of chemotherapy and radiotherapy leads to increased recruitment of DNA repair proteins while aggressive, therapy resistant cancers show overexpression of DNA repair proteins. Rad51 is a protein involved in the homologous recombination (HR) DNA repair process. Rad51 is recruited to sites of DNA damage caused by double stranded breaks, often generated by chemotherapy and radiotherapy. It is expected that inhibition of Rad51 will impair the HR repair process while enhancing the effectiveness of chemotherapy and radiotherapy compared to conventional means. As a result, this literature review aims to identify and examine the drug inhibitors of Rad51 in order to demonstrate the potential viability of this novel treatment in a variety of cancers
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