scholarly journals CTNNBIP1 modulates keratinocyte differentiation through promoting the transcription of β-catenin/TCF-complex downstream genes

2019 ◽  
Author(s):  
Chang Wang ◽  
Haizhen Wang ◽  
Youhua Peng ◽  
Bijun Zeng ◽  
Yujin Zhang ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Expression Profiles ◽  
Keratinocyte Differentiation ◽  
Hacat Cells ◽  
Online Data ◽  
Tissue Samples ◽  
Interacting Protein ◽  
Differentiation Marker ◽  
Psoriasis Lesion ◽  
Lesion Skin

Abstract Background: During psoriasis initiation and development, deregulations in signaling pathways and gene expression are observed. Methods: Herein, we downloaded seven sets of microarray mRNA expression profiles showing differentially-expressed genes in psoriasis lesion skin and non-lesion skin tissues and three sets of RNA-seq data and analyzed these online data attempting to screen for crucial genes related to keratinocyte differentiation and psoriasis development. Results: The expression of catenin beta interacting protein 1 (CTNNBIP1) was remarkably downregulated within psoriasis lesion skin tissue samples compared to that within non-lesion skin tissues based on both online data and experimental results. In response to a period of different therapies, respectively, CTNNBIP1 expression could be rescued in lesion skin tissues. Within IMQ-induced psoriasis-like dermatitis in mice, CTNNBIP1 silence further aggravated psoriatic phenotypes. In human immortalized keratinocytes, HaCaT cells, CTNNBIP1 silence significantly inhibited cell apoptosis and promoted cell proliferation. Regarding the molecular mechanism, CTNNBIP1 silence in HaCaT cells promoted β-catenin nucleus translocation, enhanced the transcriptional activity of TCF4, and increased β-catenin/TCF-complex downstream c-Myc and cyclin D1 proteins while decreased the late differentiation marker filaggrin. In contrast to CTNNBIP1, the expression of c-Myc and cyclin D1 showed to be dramatically upregulated within psoriasis lesion tissue samples than that within non-lesion tissue samples. Within tissues, c-Myc and cyclin D1 showed to be negatively correlated with CTNNBIP1, respectively. Conclusions: We identify CTNNBIP1 as an abnormally downregulated gene in psoriasis. CTNNBIP1 silence significantly disturbs the differentiation of keratinocytes through promoting the transcription of β-catenin/TCF-complex downstream genes.

scholarly journals Comprehensive analyses of competing endogenous RNA networks reveal potential biomarkers for predicting hepatocellular carcinoma recurrence

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ping Yan ◽  
Zuotian Huang ◽  
Tong Mou ◽  
Yunhai Luo ◽  
Yanyao Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
Clinical Information ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
High Rate ◽  
Competing Endogenous Rna ◽  
Tissue Samples ◽  
Potential Biomarkers

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common and deadly malignant tumors, with a high rate of recurrence worldwide. This study aimed to investigate the mechanism underlying the progression of HCC and to identify recurrence-related biomarkers. Methods We first analyzed 132 HCC patients with paired tumor and adjacent normal tissue samples from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). The expression profiles and clinical information of 372 HCC patients from The Cancer Genome Atlas (TCGA) database were next analyzed to further validate the DEGs, construct competing endogenous RNA (ceRNA) networks and discover the prognostic genes associated with recurrence. Finally, several recurrence-related genes were evaluated in two external cohorts, consisting of fifty-two and forty-nine HCC patients, respectively. Results With the comprehensive strategies of data mining, two potential interactive ceRNA networks were constructed based on the competitive relationships of the ceRNA hypothesis. The ‘upregulated’ ceRNA network consists of 6 upregulated lncRNAs, 3 downregulated miRNAs and 5 upregulated mRNAs, and the ‘downregulated’ network includes 4 downregulated lncRNAs, 12 upregulated miRNAs and 67 downregulated mRNAs. Survival analysis of the genes in the ceRNA networks demonstrated that 20 mRNAs were significantly associated with recurrence-free survival (RFS). Based on the prognostic mRNAs, a four-gene signature (ADH4, DNASE1L3, HGFAC and MELK) was established with the least absolute shrinkage and selection operator (LASSO) algorithm to predict the RFS of HCC patients, the performance of which was evaluated by receiver operating characteristic curves. The signature was also validated in two external cohort and displayed effective discrimination and prediction for the RFS of HCC patients. Conclusions In conclusion, the present study elucidated the underlying mechanisms of tumorigenesis and progression, provided two visualized ceRNA networks and successfully identified several potential biomarkers for HCC recurrence prediction and targeted therapies.

scholarly journals Overexpression of β-Arrestins inhibits proliferation and motility in triple negative breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Saber Yari Bostanabad ◽  
Senem Noyan ◽  
Bala Gur Dedeoglu ◽  
Hakan Gurdal
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Function ◽  
Expression Profiles ◽  
Tissue Samples ◽  
Expression Levels ◽  
Cell Cycle Genes

Abstractβ-Arrestins (βArrs) are intracellular signal regulating proteins. Their expression level varies in some cancers and they have a significant impact on cancer cell function. In general, the significance of βArrs in cancer research comes from studies examining GPCR signalling. Given the diversity of different GPCR signals in cancer cell regulation, contradictory results are inevitable regarding the role of βArrs. Our approach examines the direct influence of βArrs on cellular function and gene expression profiles by changing their expression levels in breast cancer cells, MDA-MB-231 and MDA-MB-468. Reducing expression of βArr1 or βArr2 tended to increase cell proliferation and invasion whereas increasing their expression levels inhibited them. The overexpression of βArrs caused cell cycle S-phase arrest and differential expression of cell cycle genes, CDC45, BUB1, CCNB1, CCNB2, CDKN2C and reduced HER3, IGF-1R, and Snail. Regarding to the clinical relevance of our results, low expression levels of βArr1 were inversely correlated with CDC45, BUB1, CCNB1, and CCNB2 genes compared to normal tissue samples while positively correlated with poorer prognosis in breast tumours. These results indicate that βArr1 and βArr2 are significantly involved in cell cycle and anticancer signalling pathways through their influence on cell cycle genes and HER3, IGF-1R, and Snail in TNBC cells.

scholarly journals Robust partial reference-free cell composition estimation from tissue expression

2020 ◽  
Vol 36 (11) ◽  
pp. 3431-3438
Author(s):  
Ziyi Li ◽  
Zhenxing Guo ◽  
Ying Cheng ◽  
Peng Jin ◽  
Hao Wu
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Real Data ◽  
Estimation Procedure ◽  
Free Cell ◽  
Biological Information ◽  
Supplementary Information ◽  
Tissue Samples ◽  
Cell Composition ◽  
Heterogeneous Tissues

Abstract Motivation In the analysis of high-throughput omics data from tissue samples, estimating and accounting for cell composition have been recognized as important steps. High cost, intensive labor requirements and technical limitations hinder the cell composition quantification using cell-sorting or single-cell technologies. Computational methods for cell composition estimation are available, but they are either limited by the availability of a reference panel or suffer from low accuracy. Results We introduce TOols for the Analysis of heterogeneouS Tissues TOAST/-P and TOAST/+P, two partial reference-free algorithms for estimating cell composition of heterogeneous tissues based on their gene expression profiles. TOAST/-P and TOAST/+P incorporate additional biological information, including cell-type-specific markers and prior knowledge of compositions, in the estimation procedure. Extensive simulation studies and real data analyses demonstrate that the proposed methods provide more accurate and robust cell composition estimation than existing methods. Availability and implementation The proposed methods TOAST/-P and TOAST/+P are implemented as part of the R/Bioconductor package TOAST at https://bioconductor.org/packages/TOAST. Contact [email protected] or [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals RNA Sequencing in Comparison to Immunohistochemistry for Measuring Cancer Biomarkers in Breast Cancer and Lung Cancer Specimens

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 114
Author(s):  
Maxim Sorokin ◽  
Kirill Ignatev ◽  
Elena Poddubskaya ◽  
Uliana Vladimirova ◽  
Nurshat Gaifullin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Rna Sequencing ◽  
Expression Profiles ◽  
Correlation Study ◽  
Cancer Tissue ◽  
Transcriptional Level ◽  
Tissue Samples ◽  
Protein Levels ◽  
Formalin Fixed Paraffin Embedded

RNA sequencing is considered the gold standard for high-throughput profiling of gene expression at the transcriptional level. Its increasing importance in cancer research and molecular diagnostics is reflected in the growing number of its mentions in scientific literature and clinical trial reports. However, the use of different reagents and protocols for RNA sequencing often produces incompatible results. Recently, we published the Oncobox Atlas of RNA sequencing profiles for normal human tissues obtained from healthy donors killed in road accidents. This is a database of molecular profiles obtained using uniform protocol and reagents settings that can be broadly used in biomedicine for data normalization in pathology, including cancer. Here, we publish new original 39 breast cancer (BC) and 19 lung cancer (LC) RNA sequencing profiles obtained for formalin-fixed paraffin-embedded (FFPE) tissue samples, fully compatible with the Oncobox Atlas. We performed the first correlation study of RNA sequencing and immunohistochemistry-measured expression profiles for the clinically actionable biomarker genes in FFPE cancer tissue samples. We demonstrated high (Spearman’s rho 0.65–0.798) and statistically significant (p < 0.00004) correlations between the RNA sequencing (Oncobox protocol) and immunohistochemical measurements for HER2/ERBB2, ER/ESR1 and PGR genes in BC, and for PDL1 gene in LC; AUC: 0.963 for HER2, 0.921 for ESR1, 0.912 for PGR, and 0.922 for PDL1. To our knowledge, this is the first validation that total RNA sequencing of archived FFPE materials provides a reliable estimation of marker protein levels. These results show that in the future, RNA sequencing can complement immunohistochemistry for reliable measurements of the expression biomarkers in FFPE cancer samples.

scholarly journals Eucalyptus citriodora extract regulates cutaneous homeostasis including immune dysregulation and skin barrier dysfunction via the modulation of peroxisome proliferator-activated receptor-delta (PPAR-delata) pathway

2019 ◽  
Vol 3 (1) ◽  
Author(s):  
Akihiro Aioi ◽  
Takuhiro Yamada
Keyword(s):  
Mrna Expression ◽  
Skin Barrier ◽  
Immune Dysregulation ◽  
Keratinocyte Differentiation ◽  
Hacat Cells ◽  
Skin Disorders ◽  
Eucalyptus Citriodora ◽  
Barrier Dysfunction ◽  
Differentiation Markers ◽  
Transfected Cells

Perturbation of cutaneous homeostasis including immune dysregulation and skin barrier dysfunction evokes skin disorders. In this study, we examined the effect of Eucalyptus citriodora (Euc-c) extract on cytokine production, cell proliferation and cell differentiation in HaCaT cells to elucidate its influence on cutaneous homeostasis. Euc-c suppressed significantly LPS-induced IL-6 and TNF-a-induced IL-8 production from HaCaT cells. Conversely IL-1ra production was significantly enhanced by Euc-c. The expressions of IVL, CERS3 and CERS4, keratinocyte differentiation markers, were upregulated to 3.1, 2.8 and 2.7-fold respectively by Euc-c treatment, compared to the control, while the proliferation was downregulated. The lipid contents in Euc-c-treated cells tended to increase, compared with non-treated cells. To explore the underlying mechanism of these effect, we next performed siRNA experiments against PPAR-b/d. Euc-c enhanced PPAR-b/d mRNA expression to 3.25-fold, while PPAR-b/d mRNA expression in transfected cells was suppressed. The expressions of IVL, CERS3 and CERS4 in transfected cells were suppressed to 1.48, 0.82 and 0.72-fold respectively, concomitant with suppression of PPAR-b/d mRNA expression. These results indicated that Euc-c exerts anti-inflammatory effects and regulates keratinocyte differentiation via the modulation of PPAR-b/d pathway. Therefore, the application of Euc-c is expected to exert beneficial effect on skin disorders evoked by perturbation of skin homeostasis.Key words: Eucalyptus citriodora, PPAR-b/d, inflammation, barrier function, cutaneous homeostasis

Identification of potential key genes in anaplastic thyroid cancer using bioinformatics analysis

2021 ◽  
Author(s):  
Zhenzhen Li ◽  
Xiong Chaoliang ◽  
Jin Wei ◽  
Ping Chen ◽  
Yanping Zhang ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Thyroid Cancer ◽  
Target Genes ◽  
Collagen Type ◽  
Expression Profiles ◽  
Thyroid Tissue ◽  
Anaplastic Thyroid Cancer ◽  
Type I ◽  
Tissue Samples ◽  
Km Plotter

Abstract Background Anaplastic thyroid cancer (ATC) has a high degree of malignancy and a poor prognosis. Its incidence accounts for approximately 10–15% of all thyroid cancers. The purpose of this study was to determine the differentially expressed genes (DEGs) of ATC through biometric analysis technology, clarify the potential interactions between them, and screen genes related to the prognosis of ATC. Methods The GSE29265, GSE65144, GSE33630, and GSE85457 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 117 tissue samples (81 normal thyroid tissue samples and 36 ATC samples). The four datasets were integrated and analyzed by the limma packages to obtain DEGs. With these DEGs, we performed gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses using the Database for Annotation, Visualization and Integrated Discovery, protein-protein interaction (PPI) analysis using Cytoscape, and survival analysis using the Kaplan-Meier (KM) plotter. Results. After R integration analysis of the four datasets, 764 DEGs were obtained, i.e., 314 upregulated and 450 downregulated genes. Among the hub DEGs obtained in the PPI network, the expression levels of thymidylate synthase (TYMS), fibronectin 1, chordin-like 1, syndecan 2, integrin alpha 2, collagen type I alpha 1 chain, collagen type IX alpha 3 chain (COL9A3), and collagen type XXIII alpha 1 chain (COL23A1) were associated with ATC prognosis. These results showed that the overall survival and recurrence-free survival of TYMS, COL9A3, and COL23A1 were statistically significant in our KM plotter survival analysis; thus, these DEGs may be used as potential biomarkers of ATC. Conclusion This study identified several potential target genes and pathways that may affect the development of ATC. These findings provide new insights for the detection of novel diagnostic and therapeutic biomarkers for ATC.

Effects of MiR-451a on the Phagocytosis and Polarization of Macrophages

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Xiaoli Liu ◽  
Dongyue Zhang ◽  
Hao Wang ◽  
Qian Ren ◽  
Lina Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Microrna Expression ◽  
Differentially Expressed ◽  
Proliferation Capacity ◽  
Microrna Sequencing ◽  
Differentiation Marker

Macrophages are important member in tissue microenvironments and play diverse physiologic and pathologic roles. Leukemia associated macrophages (LAM) are a kind of specifically activated macrophages in leukemia microenvironment, which are different from M1, M2 and TAMs. We have reported the heterogeneities in gene expression profiles of LAMs. However, MicroRNA expression profiles of LAMs and regulatory mechanism are still unknown. Here, a MLL-AF9 induced mouse acute myeloid leukemia (AML) model was used, and LAMs in the spleen and bone marrow were sorted for microRNA sequencing. The microRNA expression profiles of LAMs in bone marrow and spleen in AML mice were different from macrophages from control mice. Based on the volcano plot, more than 100 microRNAs were differentially expressed in LAMs compared with macrophages in control mice. Next, five differentially expressed microRNAs were selected and verified by qRT-PCR in LAMs from spleen. The results showed that miR-451a and miR-155-5p in spleen LAMs were significantly upregulated in LAMs from spleen. Overexpression of miR-451a altered the morphology of macrophages, enhanced the phagocytic ability of macrophages, and promotes the expression of macrophage differentiation marker CD11b. Furthermore, overexpression of miR-451a had little effect on M0 macrophages, but increased the proliferation capacity of macrophages upon stimulation toward M1 or M2 phenotype. MiR-451a overexpressed-macrophages had higher level of iNOS when stimulated with LPS or IL-4 whereas there was no difference in the expression of IL-1β, IL-6, CD206 and Arg-1 between MiR-451a overexpressed-macrophages and control macrophage. Therefore, our data revealed the characteristics of the microRNA expression profile of LAMs for the first time, and verified the effect of miR-451a on macrophage in vitro. Disclosures No relevant conflicts of interest to declare.

PTPIP51 crosslinks the NFκB signaling and the MAPK pathway in SKBR3 cells and provides a bypass mechanism for NFκB inhibition

2019 ◽  
Author(s):  
Eric Dietel ◽  
Alexander Brobeil ◽  
Claudia Tag ◽  
Stefan Gattenloehner ◽  
Monika Wimmer
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Mapk Pathway ◽  
Tyrosine Phosphatase ◽  
Large Body ◽  
Therapy Resistance ◽  
Mapk Signaling ◽  
Scaffolding Protein ◽  
Hacat Cells ◽  
Interacting Protein

Abstract Background Previous studies of our group revealed an association of the scaffolding protein Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) with the NFκB signaling on the RelA and IκB level. The NFκB signaling plays a pivotal role in many different tumor entities. Especially HER2 amplified breast cancer cells frequently display activation of the NFκB signaling. Here, the NFκB signaling is linked to the initiation, progression, and the metastasis of the breast cancer. Furthermore, a large body of evidence associates the NFκB signaling with the development of therapy resistance. We aimed to clarify the effects of NFκB inhibition on the NFκB- and the MAPK-related interactome of PTPIP51 in HaCat cells and SKBR3 cells and their correlation with cell viability. Results Both NFκB signaling inhibitors, PDTC and IKK-16, reduced the cell viability of SKBR3 cells. IKK-16 selectively reduced the cell viability in SKBR3 cells at 5µM, while the viability of HaCat cells was not affected. PDTC impaired the cell viability of both cell lines and induced a formation of the Raf1/14-3-3/PTPIP51 complex in SKBR3 cells, indicating a shift of PTPIP51 into MAPK signaling. The MAPK-related interactome of PTPIP51 remained unaffected by IKK-16. Conclusion (1)The effectiveness and selectivity of NFκB inhibition in malignant and non-malignant signaling systems depends on the level of the targeted signaling molecule. (2) PTPIP51 might serve as the mediator between the NFκB signaling and the MAPK pathway in SKBR3 cells upon NFκB inhibition.

scholarly journals P0022INNATE IMMUNE RESPONSES ELICITED BY TOLL-LIKE RECEPTORS ARE POSSIBLY INVOLVED IN THE PATHOGENESIS OF NEPHROTIC SYNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Eriko Tanaka ◽  
Ichiro Hada ◽  
Naoaki Mikami ◽  
Kunimasa Yan
Keyword(s):  
Innate Immunity ◽  
Nephrotic Syndrome ◽  
Immune System ◽  
Innate Immune System ◽  
Expression Profiles ◽  
Kidney Tissue ◽  
Innate Immune ◽  
Rna Expression ◽  
Toll Like Receptors ◽  
Tissue Samples

Abstract Background and Aims Pathogenesis of idiopathic nephrotic syndrome (INS) is yet to be fully elucidated. Immunological disorders are reported to be involved in the etiology of INS. Due to the efficacy of immunosuppressant agents such as calcineurin inhibitor and rituximab in treating nephrotic syndrome, aberrant activation of the acquired immune system through T and B cells are considered to be the underlying pathogenic mechanisms of INS. Nevertheless, there is a possibility that the innate immune system plays a key role in INS pathogenesis. This study aims to investigate the involvement of innate immunity in INS pathogenesis by examining the expressions of toll-like receptors (TLRs). Method Kidney tissue samples from two INS patients were collected at two points of time: the first biopsy was performed during nephrosis and the second during remission. Total RNA was extracted from the kidney tissue samples, and RNA-sequencing was performed to investigate RNA expression profiles. The differences between RNA expression profiles of TLRs and molecules related to TLR pathways in the tissue samples collected during nephrosis and remission were analyzed. Results There was a significant decrease in RNA expression of TLR9 and TLR10 during remission compared to nephrosis: fold change in each patient was -2.12 and -2.12 for TLR9, and -2.51 and -2.09 for TLR10. RNA expression of TLR8 also decreased: fold change in each patient was -1.19 and -1.75. There were no significant changes in the RNA expression profiles of TLR1, 2, 3, 4, 5, 6, and 7. In addition, there were no differences in the RNA expression profiles of MYD88, IRAK family, and TRAF family molecules that are associated with TLR pathways. However, RNA expressions of IL6, IL1B, IL12B, and TNF, as well as the cytokines controlled by TLR8 and TLR9 pathways, which were activated during nephrosis, disappeared or decreased during remission. Conclusion The involvement of the innate immune system in the pathogenesis of nephrotic syndrome has been suggested in some reports. Based on the fact that the onset or recurrence of nephrosis is triggered by non-specific viral infection, it is highly possible that innate immunity is involved in the pathogenesis of nephrotic syndrome. TLRs play a key role in innate immunity as they elicit the innate immune system after detecting pathogens, induce inflammatory cytokine production, and trigger signaling pathways that activate lymphocytes via maturation of dendritic cells. Specifically, TLR8, 9, and 10 mediate pathways of the first immune response to viral infections. Our study reveals that TLRs play a pivotal role in innate immunity associated with renal tissue during the onset of nephrosis.

scholarly journals Addressing cellular heterogeneity in tumor and circulation for refined prognostication

2019 ◽  
Vol 116 (36) ◽  
pp. 17957-17962 ◽  
Author(s):  
Su Bin Lim ◽  
Trifanny Yeo ◽  
Wen Di Lee ◽  
Ali Asgar S. Bhagat ◽  
Swee Jin Tan ◽  
...  
Keyword(s):  
Risk Model ◽  
Expression Profiles ◽  
Metastatic Potential ◽  
Cellular Heterogeneity ◽  
Intratumor Heterogeneity ◽  
Specific Gene ◽  
Label Free ◽  
Tissue Samples ◽  
Inertial Focusing ◽  
Gene Signatures

Despite pronounced genomic and transcriptomic heterogeneity in non–small-cell lung cancer (NSCLC) not only between tumors, but also within a tumor, validation of clinically relevant gene signatures for prognostication has relied upon single-tissue samples, including 2 commercially available multigene tests (MGTs). Here we report an unanticipated impact of intratumor heterogeneity (ITH) on risk prediction of recurrence in NSCLC, underscoring the need for a better genomic strategy to refine prognostication. By leveraging label-free, inertial-focusing microfluidic approaches in retrieving circulating tumor cells (CTCs) at single-cell resolution, we further identified specific gene signatures with distinct expression profiles in CTCs from patients with differing metastatic potential. Notably, a refined prognostic risk model that reconciles the level of ITH and CTC-derived gene expression data outperformed the initial classifier in predicting recurrence-free survival (RFS). We propose tailored approaches to providing reliable risk estimates while accounting for ITH-driven variance in NSCLC.

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