scholarly journals Deep Learning Analyses to Delineate the Molecular Remodeling Process after Myocardial Infarction

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3268
Author(s):  
Oriol Iborra-Egea ◽  
Carolina Gálvez-Montón ◽  
Cristina Prat-Vidal ◽  
Santiago Roura ◽  
Carolina Soler-Botija ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Epithelial Mesenchymal Transition ◽  
Experimental Information ◽  
Machine Learning Algorithms ◽  
Infarct Core ◽  
Mesenchymal Transition ◽  
Mechanistic Analysis ◽  
Comprehensive Picture ◽  
Adverse Remodeling ◽  
Specific Proteins

Specific proteins and processes have been identified in post-myocardial infarction (MI) pathological remodeling, but a comprehensive understanding of the complete molecular evolution is lacking. We generated microarray data from swine heart biopsies at baseline and 6, 30, and 45 days after infarction to feed machine-learning algorithms. We cross-validated the results using available clinical and experimental information. MI progression was accompanied by the regulation of adipogenesis, fatty acid metabolism, and epithelial–mesenchymal transition. The infarct core region was enriched in processes related to muscle contraction and membrane depolarization. Angiogenesis was among the first morphogenic responses detected as being sustained over time, but other processes suggesting post-ischemic recapitulation of embryogenic processes were also observed. Finally, protein-triggering analysis established the key genes mediating each process at each time point, as well as the complete adverse remodeling response. We modeled the behaviors of these genes, generating a description of the integrative mechanism of action for MI progression. This mechanistic analysis overlapped at different time points; the common pathways between the source proteins and cardiac remodeling involved IGF1R, RAF1, KPCA, JUN, and PTN11 as modulators. Thus, our data delineate a structured and comprehensive picture of the molecular remodeling process, identify new potential biomarkers or therapeutic targets, and establish therapeutic windows during disease progression.

scholarly journals Histone methyltransferase SETD1A participates in lung cancer progression

2020 ◽  
Author(s):  
Mei Du ◽  
Piping Gong ◽  
Yun Zhang ◽  
Yanguo Liu ◽  
Xiaozhen Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Normal Lung ◽  
Control Group ◽  
Cancer Tissue ◽  
Mesenchymal Transition ◽  
Cancer Symptoms ◽  
Mechanistic Analysis

Abstract Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and TGFβ pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

scholarly journals Histone methyltransferase SETD1A participates in lung cancer progression

2020 ◽  
Author(s):  
Mei Du ◽  
Xiuwen Wang ◽  
Piping Gong ◽  
Yun Zhang ◽  
Yanguo Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Normal Lung ◽  
Control Group ◽  
Cancer Tissue ◽  
Mesenchymal Transition ◽  
Cancer Symptoms ◽  
Mechanistic Analysis

Abstract Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~ 15%, which is attributed to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and TGFβ pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

scholarly journals Effects of DSPP and MMP20 Silencing on Adhesion, Metastasis, Angiogenesis, and Epithelial-Mesenchymal Transition Proteins in Oral Squamous Cell Carcinoma Cells

2020 ◽  
Vol 21 (13) ◽  
pp. 4734
Author(s):  
Jaya Aseervatham ◽  
Kalu U.E. Ogbureke
Keyword(s):  
Squamous Cell ◽  
Epithelial Mesenchymal Transition ◽  
Integrin Αvβ3 ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Function Mechanism ◽  
Cancer Cell Adhesion ◽  
Specific Proteins ◽  
E Cadherin

Recent reports highlight the potential tumorigenic role of Dentin Sialophosphoprotein (DSPP) and its cognate partner Matrix Metalloproteinase 20 (MMP-20) in Oral Squamous Cell Carcinomas (OSCCs). However, the function/mechanism of these roles is yet to be fully established. The present study aimed to investigate the effects of DSPP and MMP20 silencing on specific proteins involved in oral cancer cell adhesion, angiogenesis, metastasis, and epithelial-mesenchymal transition (EMT). Stable lines of DSPP/MMP20 silenced OSCC cell line (OSC2), previously established via lentiviral-mediated shRNA transduction, were analyzed for the effects of DSPP, MMP20, and combined DSPP–MMP20 silencing on MMP2, MMP9, integrins αvβ3 and αvβ6, VEGF, Kallikerin- 4,-5,-8,-10, E-cadherin, N-cadherin, Vimentin, met, src, snail, and Twist by Western blot. Results show a significant decrease (p < 0.05) in the expression of MMP2, MMP9, integrin αvβ3, αvβ6, VEGF, Kallikerins -4, -5, -8, -10, N-cadherin, vimentin met, src, snail and twist following DSPP and MMP20 silencing, individually and in combination. On the other hand, the expression of E-cadherin was found to be significantly increased (p < 0.05). These results suggest that the tumorigenic effect of DSPP and MMP20 on OSC2 cells is mediated via the upregulation of the genes involved in invasion, metastasis, angiogenesis, and epithelial-mesenchymal transition (EMT).

scholarly journals The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis

2021 ◽  
Vol 22 (7) ◽  
pp. 3591
Author(s):  
Eunjeong Kang ◽  
Jihye Seo ◽  
Haelim Yoon ◽  
Sayeon Cho
Keyword(s):  
Wound Healing ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Translational Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Down Regulation ◽  
Mesenchymal Transition ◽  
Specific Proteins

Epithelial–mesenchymal transition (EMT) is generally observed in normal embryogenesis and wound healing. However, this process can occur in cancer cells and lead to metastasis. The contribution of EMT in both development and pathology has been studied widely. This transition requires the up- and down-regulation of specific proteins, both of which are regulated by EMT-inducing transcription factors (EMT-TFs), mainly represented by the families of Snail, Twist, and ZEB proteins. This review highlights the roles of key EMT-TFs and their post-translational regulation in cancer metastasis.

scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

2020 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
Vanessa Núñez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

ABSTRACTMacrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

scholarly journals The Role of ATRA, Natural Ligand of Retinoic Acid Receptors, on EMT-Related Proteins in Breast Cancer: Minireview

2021 ◽  
Vol 22 (24) ◽  
pp. 13345
Author(s):  
Pavel Bobal ◽  
Marketa Lastovickova ◽  
Janette Bobalova
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Natural Ligand ◽  
All Trans Retinoic Acid ◽  
Specific Proteins ◽  
Diagnostic Approaches ◽  
Related Proteins ◽  
The Impact

The knowledge of the structure, function, and abundance of specific proteins related to the EMT process is essential for developing effective diagnostic approaches to cancer with the perspective of diagnosis and therapy of malignancies. The success of all-trans retinoic acid (ATRA) differentiation therapy in acute promyelocytic leukemia has stimulated studies in the treatment of other tumors with ATRA. This review will discuss the impact of ATRA use, emphasizing epithelial-mesenchymal transition (EMT) proteins in breast cancer, of which metastasis and recurrence are major causes of death.

scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Ana Paredes ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

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