scholarly journals Sex-dependent gene co-expression in the human body

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Robin J. G. Hartman ◽  
Michal Mokry ◽  
Gerard Pasterkamp ◽  
Hester M. den Ruijter
Keyword(s):  
Sex Differences ◽  
Human Body ◽  
Gene Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Tissue Expression ◽  
Whole Body ◽  
Sequencing Data ◽  
Disease Etiology ◽  
Mesenchymal Transition ◽  
Approved Drugs

AbstractMany pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene co-expression map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 29.5% of the gene co-expression is influenced by sex. For example, skeletal muscle was predominantly enriched with genes co-expressed stronger in males, whereas thyroid primarily contained genes co-expressed stronger in females. This was accompanied by consistent sex differences in pathway enrichment, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene co-expression over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are associated with sex-biased diseases, such as autoimmunity and cancer, and more often the target of FDA-approved drugs than non-sexbiased genes. Our study suggests that sex affects biological gene networks by differences in gene co-expression and that attention to the effect of sex on biological responses to medical drugs is warranted.

scholarly journals Sex dependent gene activity in the human body

2020 ◽  
Author(s):  
Robin J.G. Hartman ◽  
Michal Mokry ◽  
Gerard Pasterkamp ◽  
Hester M. den Ruijter
Keyword(s):  
Sex Differences ◽  
Systems Biology ◽  
Human Body ◽  
Epithelial To Mesenchymal Transition ◽  
Tissue Expression ◽  
Gene Activity ◽  
Whole Body ◽  
Sequencing Data ◽  
Disease Etiology ◽  
Mesenchymal Transition

AbstractMany pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene activity map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 20.1% of the gene activity is influenced by sex. For example, skeletal muscle was predominantly enriched with genes more active in males, whereas thyroid primarily contained genes more active in females. This was accompanied by consistent sex differences in pathway activity, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene activity over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are known druggable targets. This emphasizes sex as a biological variable and the need to incorporate sex in systems biology studies.

scholarly journals Vimentin as a target for the treatment of COVID-19

2020 ◽  
Vol 7 (1) ◽  
pp. e000623
Author(s):  
Zhenlin Li ◽  
Denise Paulin ◽  
Patrick Lacolley ◽  
Dario Coletti ◽  
Onnik Agbulut
Keyword(s):  
Viral Infection ◽  
Lung Inflammation ◽  
Epithelial To Mesenchymal Transition ◽  
Attachment Site ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Cellular Target ◽  
Innovative Idea ◽  
Life Threatening ◽  
Approved Drugs

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.

scholarly journals Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2823
Author(s):  
Ian M. Overton ◽  
Andrew H. Sims ◽  
Jeremy A. Owen ◽  
Bret S. E. Heale ◽  
Matthew J. Ford ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Cell Model ◽  
Tumour Progression ◽  
Mesenchymal Transition ◽  
Transcription Factor Target ◽  
Network Modules ◽  
Conserved Gene

Cell identity is governed by gene expression, regulated by transcription factor (TF) binding at cis-regulatory modules. Decoding the relationship between TF binding patterns and gene regulation is nontrivial, remaining a fundamental limitation in understanding cell decision-making. We developed the NetNC software to predict functionally active regulation of TF targets; demonstrated on nine datasets for the TFs Snail, Twist, and modENCODE Highly Occupied Target (HOT) regions. Snail and Twist are canonical drivers of epithelial to mesenchymal transition (EMT), a cell programme important in development, tumour progression and fibrosis. Predicted “neutral” (non-functional) TF binding always accounted for the majority (50% to 95%) of candidate target genes from statistically significant peaks and HOT regions had higher functional binding than most of the Snail and Twist datasets examined. Our results illuminated conserved gene networks that control epithelial plasticity in development and disease. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington’s epigenetic landscape during epithelial remodelling. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology, with implications for precision medicine. Predicted invasion roles were validated using a tractable cell model, supporting our approach.

scholarly journals Prognostic Role of the MicroRNA-200 Family in Various Carcinomas: A Systematic Review and Meta-Analysis

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jung Soo Lee ◽  
Young-Ho Ahn ◽  
Hye Sung Won ◽  
Der Sheng Sun ◽  
Yeo Hyung Kim ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Meta Analysis ◽  
Family Members ◽  
Progression Free Survival ◽  
Tissue Expression ◽  
Free Survival ◽  
Mesenchymal Transition ◽  
Hazard Ratios ◽  
Cancer Types

Background/Aims.The miRNA-200 (miR-200) family may act as key inhibitors of epithelial-to-mesenchymal transition. However, the potential prognostic value of miR-200s in various human malignancies remains controversial. This meta-analysis analyzed the associations between miR-200 levels and survival outcomes in a variety of tumors.Methods.Eligible published studies were identified by searching the Embase, PubMed, CINAHL, and Google scholar databases. Patient clinical data were pooled, and pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to calculate the strength of this association.Results.The pooled HRs suggested that high tissue expression of miR-200 family members was associated with better survival (overall survival [OS]: HR = 0.70, 95% CI 0.54–0.91; progression-free survival [PFS]: HR = 0.63, 95% CI 0.52–0.76) in thirty-four eligible articles. In contrast, higher expression of circulating miR-200 members was significantly associated with poor clinical outcome (OS, HR = 1.68, 95% CI 1.15–2.46; PFS, HR = 2.62, 95% CI 1.68–4.07).Conclusion.The results from this meta-analysis suggest that miR-200 family members are potential prognostic biomarkers in patients with various carcinomas. To apply these findings in the clinic, large prospective studies are needed to validate the prognostic values of miR-200s in individual cancer types.

scholarly journals Glycosyltransferase ST6Gal-I promotes the epithelial to mesenchymal transition in pancreatic cancer cells

2020 ◽  
pp. jbc.RA120.014126
Author(s):  
Colleen M Britain ◽  
Nikita Bhalerao ◽  
Austin D Silva ◽  
Asmi Chakraborty ◽  
Donald J Buchsbaum ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Gene Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Pancreatic Cancer Cell Line ◽  
Membrane Receptors ◽  
Cell Phenotype ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Cell Invasiveness ◽  
St6gal I

ST6Gal-I, an enzyme upregulated in numerous malignancies, adds α2-6-linked sialic acids to select membrane receptors, thereby modulating receptor signaling and cell phenotype. In this study, we investigated ST6Gal-I’s role in epithelial to mesenchymal transition (EMT) using the Suit2 pancreatic cancer cell line, which has low endogenous ST6Gal-I and limited metastatic potential, along with two metastatic Suit2-derived subclones, S2-013 and S2-LM7AA, which have upregulated ST6Gal-I. RNA-Seq results suggested that the metastatic subclones had greater activation of EMT-related gene networks than parental Suit2 cells, and forced overexpression (OE) of ST6Gal-I in the Suit2 line was sufficient to activate EMT pathways. Accordingly, we evaluated expression of EMT markers and cell invasiveness (a key phenotypic feature of EMT) in Suit2 cells with or without ST6Gal-I OE,  as well as S2-013 and S2-LM7AA cells with or without ST6Gal-I knockdown (KD). Cells with high ST6Gal-I expression displayed enrichment in mesenchymal markers (N-cadherin, slug, snail, fibronectin) and cell invasiveness, relative to ST6Gal-I-low cells. Contrarily, epithelial markers (E-cadherin, occludin) were suppressed in ST6Gal-I-high cells. To gain mechanistic insight into ST6Gal-I’s role in EMT, we examined the activity of EGFR, a known EMT driver. ST6Gal-I-high cells had greater α2-6 sialylation and activation of EGFR than ST6Gal-I-low cells. The EGFR inhibitor, erlotinib, neutralized ST6Gal-I-dependent differences in EGFR activation, mesenchymal marker expression and invasiveness in Suit2 and S2-LM7AA, but not S2-013, lines. Collectively, these results advance our understanding of ST6Gal-I’s tumor-promoting function by highlighting a role for ST6Gal-I in EMT, which may be mediated, at least in part, by α2-6-sialylated EGFR.

scholarly journals TMOD-25. IN VIVO MODEL OF TREATMENT-RESISTANT GLIOBLASTOMA HIGHLIGHTS SEX DIFFERENCES IN SURVIVAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii233-ii233
Author(s):  
Mona Al-Gizawiy ◽  
Robert Wujek ◽  
Melissa Prah ◽  
Salvatore Molino ◽  
Christopher Chitambar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Sex Differences ◽  
Epithelial To Mesenchymal Transition ◽  
Response To Therapy ◽  
In Vivo Model ◽  
Testing System ◽  
Treatment Resistant ◽  
Male And Female ◽  
Mesenchymal Transition

Abstract BACKGROUND Sex differences independent from acute hormone action are evident in the incidence and tumorigenesis of several cancers, including glioblastoma (GBM). Malignant brain tumors with mesenchymal, proneural, and neural GBM subtypes occur twice as frequently in males than in females, implying a molecular basis for the sex disparities observed. Accordingly, response to therapy and overall survival, may also differ between male and female GBM patients. Further elucidation of these differences would benefit from a robust preclinical testing system, such as the one described here. METHODS Adult (U87-MG) GBM cells were exposed to a total radiation dose of 10 Gy, effecting an epithelial to mesenchymal transition. The resultant irradiated U87-10Gy cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. In vivo advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics™ Software (IQ-AI, Ltd.). RESULTS Tumor take was 90% in males and 60% in females, indicating an ‘incidence’ ratio of 1.5. Overall survival was significantly higher in females (median = 48, range = 40-72 days) than in males (median = 28, range = 27-30 days) (p = 0.024). Immunohistochemical and imaging analyses are pending and will be discussed. CONCLUSION The outcomes noted in this pilot study mirror incidence and survival outcomes noted in GBM patients undergoing standard care. Our model of treatment-resistant glioma provides a robust testing system to study underlying sex differences in GBM biology and treatment response in parallel analyses of male and female data.

scholarly journals Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 135
Author(s):  
Panagiotis J. Vlachostergios ◽  
Athanasios Karathanasis ◽  
Vassilios Tzortzis
Keyword(s):  
Prostate Cancer ◽  
Mrna Expression ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Activation Protein ◽  
Castration Resistant Prostate Cancer ◽  
Sequencing Data ◽  
Clinical Value ◽  
Mesenchymal Transition ◽  
Fibroblast Activation ◽  
Neuroendocrine Prostate Cancer

Background: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. Methods: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. Results: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). Conclusions: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

scholarly journals A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer

NAR Cancer ◽  
2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Eirik Høye ◽  
Bastian Fromm ◽  
Paul H M Böttger ◽  
Diana Domanska ◽  
Annette Torgunrud ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Metastatic Progression ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Mesenchymal Transition ◽  
Starting Point ◽  
Microrna Sequencing ◽  
Metastatic Sites

ABSTRACT Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published next-generation sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as up-regulated at multiple metastatic sites Mir-210_3p, Mir-191_5p, Mir-8-P1b_3p [mir-141–3p], Mir-1307_5p and Mir-155_5p. Several have previously been implicated in metastasis through involvement in epithelial-to-mesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.

scholarly journals Identification of Hepatic Fibrosis Inhibitors Through Morphometry Analysis of Hepatic Multicellular Spheroids Models

2020 ◽  
Author(s):  
Haengran Seo ◽  
Yeonhwa Song ◽  
Jinyeong Heo ◽  
David Shum ◽  
Su-Yeon Lee ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Hepatic Fibrosis ◽  
High Throughput Screening ◽  
Epithelial To Mesenchymal Transition ◽  
New Drugs ◽  
Multicellular Spheroids ◽  
Mesenchymal Transition ◽  
Morphometry Analysis ◽  
Endothelial To Mesenchymal Transition ◽  
Approved Drugs

Abstract Background: A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. Methods: In this study, we aimed to identify potential mechanisms and inhibitors of fibrosis using 3D model-based phenotypic screening. We established liver fibrosis models using multicellular tumor spheroids (MCTSs) composed of hepatocellular carcinoma (HCC) and stromal cells such as fibroblasts (WI38), hepatic stellate cells (LX2), and endothelial cells (HUVEC) seeded at constant ratios. Results: Through high-throughput screening of FDA-approved drugs, we identified retinoic acid and forskolin as candidates to attenuate the compactness of MCTSs as well as inhibit the expression of ECM-related proteins. Additionally, retinoic acid and forskolin induced reprogramming of fibroblast and cancer stem cells in the HCC microenvironment. Of interest, retinoic acid and forskolin had anti-fibrosis effects by decreasing expression of a-SMA and F-actin in LX2 cells and HUVEC cells. Moreover, when sorafenib was added along with retinoic acid and forskolin, apoptosis was increased, suggesting that anti-fibrosis drugs may improve tissue penetration to support the efficacy of anti-cancer drugs. Conclusion: Collectively, these findings support the potential utility of morphometric analyses of hepatic multicellular spheroid models in the development of new drugs with novel mechanisms for the treatment of hepatic fibrosis and HCCs.

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