Epithelial-mesenchymal Transition Signaling Pathway Research Articles

Identification of microRNA and gene interactions through bioinformatic integrative analysis for revealing candidate signatures in prostate cancer

BackgroundProstate cancer (PCa) is a most common diagnosed cancer among males globally. Despite the decreased PCa mortality, increased prevalence of it creates huge burden on the population. MicroRNAs (miRNAs) are class of endogenous, non-coding, single stranded RNAs having ~22–24 bases. They work at the posttranscriptional gene regulation. MiRNAs have been seen in various in-vivo biological processes, including proliferation, apoptosis, migration, invasion, as well as epithelial-mesenchymal transition (EMT). MethodologyTwo miRNA expression datasets GSE76260, GSE60117 and one mRNA expression dataset GSE69223 from GEO (Gene Expression Omnibus) were included in this study for enrichment analysis. We identified total of 255 significant upregulated differentially expressed miRNAs (DEMs) and 339 significant downregulated DEMs from GSE78260 and GSE60117 datasets. 898 significant upregulated differentially expressed genes (DEGs) and 1486 significant downregulated DEGs from GSE69223 datasets in PCa vs normal prostate tissues. ResultsThe Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis for the key DEMs revealed that insulin signaling pathway, MAPK signaling pathway, EMT signaling pathway etc. are the most significant pathways, while KEGG pathway enrichment analysis for the DEGs demonstrated that steroid biosynthesis and focal adhesion are the most significant pathways involved in PCa carcinogenesis. The DEMs including hsa-miR-140-5p, hsa-miR-320b, hsa-miR-369-3p, hsa-miR-450b-5p, hsa-miR-483-3p, hsa-miR-532-3p and hsa-miR-576-5p identified as a key regulatory miRNA. Furthermore, DEGs including EGF, BMP2, FGF2, IGF1, CDH2 identified as the hub genes in the PPI network. Interestingly, key regulator miRNAs were significantly associated with ROC analysis. ConclusionIn this study, these identified key regulatory miRNAs and hub genes may be useful as a diagnostic and prognostic biomarker in PCa, may have contributing role in PCa pathogenesis. Moreover, the identified pathway may be potential therapeutical targets in PCa.

Serum Extracellular Nano-Vesicles miR-153-3p to Identify Micronodular Lung Cancer from Sub-Centimeter Lung Nodules.

Identification of malignancy from sub-centimeter lung nodules (LNs, <1 cm) is core for prevention and treatment of primary phases of lung cancer (LC). The study's purpose was to predict micro-nodular lung cancer (mnLC), such as adenocarcinoma in situ (AIS), micro-invasive adenocarcinoma (MIA), and invasive adenocarcinoma stage 1 (IA1) based on serum extracellular nano-vesicles (sEVs) miR-153-3p. sEVs-miR-153-3p was selected in this study and then used to investigate the expression and efficacy by RT-qPCR in the validation phase, followed by sEVs derived from patients of mnLC, benign lung nodule (BLN), and healthy people groups comprised of 135 recruiters. Further, the study established the prediction model which combined sEVs-miR-153-3p expression with multiple clinical-radiomics features by Logistic algorithms and was authenticated by the area under curve (AUC) phenomenon. Then, a simple-to-use nomogram was developed by Cox proportional-hazards regression modeling for predicting mnLC. Besides, in vitro analyses were performed to demonstrate miR-153-3p/ROCK1 axis in regulating biological mechanisms using LC cell lines. Results demonstrated that sEVs-miR-153-5p's expression values were higher in mnLC patients compared to BLN and healthy people. The prediction model for mnLC was successfully established, utilizing sEVs-miR-153-5p biomarker with significant clinical-radiomics features and yielding an AUC = 0.943 (95%CI: 0.898~0.989, P <0.0001). Moreover, the miR-153-3p and its targeted gene ROCK1 were confirmed as down-regulated in NSCLC cell lines and up-regulated expression respectively. Moreover, the miR-153-3p/ROCK1 axis took part in promoting the epithelial-mesenchymal transition (EMT) signaling pathway and regulated certain biological functions, such as proliferation, migration and invasion of LC cells. Therefore, the sEVs-miR-153-3p associated with radiomics-clinical features showed enormous potential to non-invasively identify malignancy from subcentimeter LNs. miR-153-3p could promote the genesis and progress of LC via EMT signaling pathway, which may serve as a therapeutic target.

S100A4/TCF Complex Transcription Regulation Drives Epithelial-Mesenchymal Transition in Chronic Sinusitis Through Wnt/GSK-3β/β-Catenin Signaling.

Epithelial-mesenchymal transition (EMT) is thought to be involved in the tissue remodeling and long-term inflammatory process of chronic sinusitis (CRS), but the driving mechanism is still unclear. Using high-resolution mass spectrometry, we performed a proteomic screen of CRS nasal mucosal tissue to identify differentially expressed proteins. Data are available via ProteomeXchange with identifier PXD030884. Specifically, we identified S100 calcium binding protein A4 (S100A4), an effective factor in inflammation-related diseases, and its downstream protein closely related to tissue fibrosis collagen type I alpha 1 chain (COL1A1), which suggested its involvement in nasal mucosal tissue remodeling. In addition, stimulation of human nasal epithelial cells (HNEpCs) with lipopolysaccharide (LPS) mimicked the inflammatory environment of CRS and showed that S100A4 is involved in regulating EMT and thus accelerating tissue remodeling in the nasal mucosa, both in terms of increased cell motility and overexpression of mesenchymal-type proteins. Additionally, we further investigated the regulation mechanism of S100A4 involved in EMT in CRS. Our research results show that in the inflammatory environment of CRS nasal mucosal epithelial cells, TCF-4 will target to bind to S100A4 and regulate its transcription. The transcription of S100A4 in turn affects the execution of the important signaling pathway in EMT, the Wnt/GSK-3β/β-catenin pathway, through the TCF-4/β-catenin complex. In conclusion, this study confirmed that the expression of S100A4 was significantly increased during the progressive EMT process of CRS mucosal epithelial cells, and revealed that the transcriptional regulation of S100A4 plays an important role in the occurrence and development of EMT. This finding will help us to better understand the pathogenesis behind the remodeling in CRS patients, and identify target molecules for the treatment of CRS.

Berberine inhibits the proliferation of pancreatic cancer cells by targeting pancreatic cancer stem cells through regulating EMT signaling pathway

Pancreatic ductal adenocarcinoma (PDAC) is universally acknowledged as the cancer with the highest mortality rate. Berberine has high medicinal value and has been used as an anti-cancer agent. Hence the purpose of this study was to investigate the anti-cancer effect of berberine in PDAC. Berberine was shown to have a selective anti-cancer effect on PDAC by MTT assay in vitro. Pancreatic cancer stem cells (PCSCs), regulated by epithelial–mesenchymal transition (EMT), could promote the proliferation of PDAC cells. However, berberine suppressed the proliferation and stemness of PCSCs through immunofluorescence staining, stem cell sphere assays and so forth in vitro. In vivo, berberine reduced tumor size and decreased the expression levels of Ki67, a marker of cellular proliferation, in orthotopic pancreatic tumors. In addition, berberine inhibited the EMT signaling pathway by RT-PCR and Western blotting methods both in vitro and in vivo. Our study indicates that berberine inhibits the proliferation of PDAC cells both in vivo and in vitro. The mechanism of the anti-cancer effect of berberine likely involves the inhibition of EMT. Therefore, berberine may be a novel antineoplastic drug with clinical efficacy in PDAC.

Circrna ABCB10 promotes cell proliferation and invasion by affecting emt signaling pathway in cervical cancer

Recently, many emerging circular RNAs (circRNAs) have been studied in human malignancies including cervical cancer and are involved in tumor development and oncogenesis. Here, we found that circABCB10 was higher in 58 cervical cancer tissue sample than that in the adjacent normal tissues. Higher circABCB10 expression significantly associated with advanced the International Federation of Gynecology and Obstetrics (FIGO) stage and greater lymphatic invasion, and worse survival time in cervical cancer patients. Function assays showed that circABCB10 silencing inhibited cell proliferation, migration and invasion capacities. Moreover, we demonstrated that inhibition of circABCB10 upregulated epithelial-mesenchymal transition (EMT)-related proteins E-cadherin expression and downregulated the Vimentin expression, which suggested that affected EMT signaling pathway in cervical cancer. Thus, the circABCB10 may contribute to the development of cervical cancer by affecting epithelial-mesenchymal transition signaling pathways.

Chronic cadmium exposure induces epithelial mesenchymal transition in prostate cancer cells through a TGF-β-independent, endoplasmic reticulum stress induced pathway

In this study, we aimed to elucidate the role of chronic cadmium (Cd) exposure in epithelial-mesenchymal transition (EMT) and thus malignant phenotypic changes of prostate cancer cells. Prostate cancer cells (PC-3 and DU145) were exposed to a non-toxic level (0.5 or 2 μM) of Cd for up to 3 months, which resulted in significantly promoted migration and invasion of the cells. These phenotypic changes were considered to be the consequence of enhanced EMT as evidenced by diminished expression of E-cadherin and increased vimentin expression. Regarding the mechanisms of Cd-induced EMT, we found Smad3 was activated but without upregulation of TGF-β. Alternatively, we found endoplasmic reticulum (ER) stress of prostate cancer cells was significantly evoked, which was parallel with the increased reactive oxygen species (ROS). Removal of ROS by N-acetylcysteine significantly reduced ER stress in prostate cancer cells, followed by the decrease of Smad3 phosphorylation and expression of nuclear Snail, resulting in the inhibition of EMT and malignant phenotypic changes of prostate cancer cells. These findings indicated a new TGF-β independent, ROS-mediated ER stress/Smad signaling pathway in chronic Cd exposure-induced EMT of prostate cancer cells, which could be a novel mechanism involved in cadmium-mediated cancer cells malignant transformation. Accordingly, ROS-induced ERs may become a novel preventive and therapeutic target for cancer.

Comparative mRNA/micro-RNA co-expression network drives melanomagenesis by promoting epithelial–mesenchymal transition and vasculogenic mimicry signaling

This study aimed to identify a novel disease-associated differentially co-expressed mRNA-microRNA (miRNA) that is associated with vasculogenic mimicry (VM) and epithelial-to-mesenchymal transition (EMT) network at different stages of melanoma. By applying weighted gene co-expression network analysis, we constructed a VM+EMT biological network with the available microarray dataset downloaded from a public database. Quantitative real-time PCR, immunohistochemical staining, and CD31-periodic acid solution dual staining were performed to confirm the expression of genes associated with EMT and VM formation in subjects with malignant melanoma (n = 18) and primary melanoma (n = 13) and in healthy subjects (n = 10). Our findings suggested that phosphatidylserine-specific phospholipase A1-alpha (PLA1A) and dermokine (DMKN) genes function as oncogenes that trigger VM and EMT processes during melanomagenesis on interaction with miR-370, miR-563, and miR-770–5p. PLA1A and DMKN genes can be considered potential VM+EMT network-based diagnostic biomarkers for distinguishing between melanoma patients. We postulate that a network with altered PLA1A/miR-563 and DMNK/miR-770–5p/miR-370 may contribute to melanomagenesis by triggering the EMT signaling pathway and VM formation. This study provides a potentially valuable approach for the early diagnosis and prognosis of melanoma progression.

MicroRNA-34a Alleviates Gemcitabine Resistance in Pancreatic Cancer by Repression of Cancer Stem Cell Renewal.

This study aimed to enhance the sensitivity of pancreatic ductal adenocarcinoma cells by microRNA-34a (miR-34a)-mediated targeting of Notch 1. Cell viability was determined by using an MTT (3-(4,5)-dimethylthiahiazo(-2)-3,5-diphenytetrazoliumromide) assay. The expression levels of miR-34a and relevant mRNAs were determined using quantitative polymerase chain reaction. Protein levels were measured by Western blotting. Cellular stemness was assessed by cell invasiveness and sphere formation assays. A transplanted tumor model was established for in vivo experiments. MicroRNA-34a enhanced gemcitabine sensitivity both in vivo and in vitro. MicroRNA-34a suppressed the stemness and proliferation of pancreatic cancer stem cells. MicroRNA-34a directly associated with Notch 1, which lies upstream of epithelial-mesenchymal transition signaling pathways. MicroRNA-34a sensitized pancreatic cancer cells to gemcitabine treatment by inhibiting Notch 1 signaling in pancreatic cancer stem cells, indicating that miR-34a has the potential to be developed as a novel therapeutic agent for the treatment of gemcitabine-resistant pancreatic ductal adenocarcinoma cells.

Silencing of Long Non-coding RNA HOTAIR Suppresses Reverses Epithelial-Mesenchymal Transition in AGS Gastric Cancer Cell Line by Downregulation of Fibronectin 1 and Claudin-4

Background: Gastric cancer is the second reason for cancer mortality worldwide, with a high capacity for metastasis. Long non-coding RNAs (lncRNAs) are recently described as lengthy transcripts with no open reading frame. The lncRNAs play an important role in critical cellular and molecular pathways, including cell cycle, growth, differentiation, and apoptosis. Therefore, it is not surprising that abnormal expression of lncRNAs may be involved in human cancers. The HOX antisense intergenic RNA (HOTAIR) is a highly cited lncRNAs whose altered expression has been reported in a variety of human cancers such as gastric cancer. Epithelial to mesenchymal transition (EMT) is a cellular route in which an epithelial phenotype of the cells can be changed into the mesenchymal state. The signaling pathways involved in EMT are related to cancer metastasis and recurrence of gastric cancer. Methods: The present study was aimed to investigate the effect of HOTAIR gene silencing on expression levels of fibronectin 1 (FN1) and claudin-4 (CLDN4) genes, two important markers of EMT, in AGS cellular model of gastric cancer. The AGS cells were exposed to the HOTAIR-specific siRNA for 48 hours. The extracted RNAs were subjected to complementary DNA synthesis and real-time PCR. Data were analyzed using 2−ΔΔCt method. Cells with no siRNA treatment were considered the control set. The P-value &lt; 0.05 was considered statistically significant. Results: The observed data showed that the expression levels of two EMT markers FN1 and CLDN4, were significantly decreased after HOTAIR silencing. Conclusions: This study demonstrates that HOTAIR can regulate the EMT signaling pathway through critical EMT factors like FN1 and CLDN4 transcripts. However, a long way remains to apply this finding in therapeutic approach, and further experiments are needed.

MTHFD2 promotes ovarian cancer growth and metastasis via activation of the STAT3 signaling pathway.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. MTHFD2 has been reported to be overexpressed in several malignant tumors and is implicated in cancer development. This study aimed to investigate the effect of MTHFD2 on ovarian cancer progression. The expression of MTHFD2 was detected by bioinformatic analysis, immunohistochemistry, RT‐qPCR (real‐time quantitative PCR analysis), and western blot analysis. The effects of MTHFD2 depletion on cell proliferation, migration, and invasion were determined through in vitro experiments. Cell cycle progression and apoptosis were accessed by flow cytometry. The related signaling pathway protein expression was determined by western blot analysis. We found that MTHFD2 is highly expressed in both ovarian cancer tissues and cell lines. MTHFD2 deletion suppressed cell proliferation and metastasis. Knockdown of MTHFD2 induces cell apoptosis and G2/M arrest, whereas the number of cells in S phase increased with MTHFD2 overexpression. Mechanically, our results indicate that an inhibitory effect of MTHFD2 knockdown may be mediated by the downregulation of cyclin B1/Cdc2 complex and the inhibitory effect on its activity. Additionally, MTHFD2 could regulate cell growth and aggressiveness via activation of STAT3 and the STAT3‐induced epithelial–mesenchymal transition signaling pathway. These findings indicate that MTHFD2 is overexpressed in ovarian cancer and regulates cell proliferation and metastasis, presenting an attractive therapeutic target.

ISLR affects colon cancer progression by regulating the epithelial-mesenchymal transition signaling pathway.

This study aims to determine the mechanism of ISLR on the progression of colon cancer. TCGA database was used to analyze ISLR expression in colon cancer tumor tissues. QRT-PCR and western blotting were used to detect ISLR expression in colon cancer cells. CCK-8, colony formation, EDU, wound healing and transwell assays were used to measure cell viability, proliferation, migration and invasion of colon cancer cells, respectively. The signaling pathway enrichment analysis of ISLR was analyzed on the basis of the KEGG database. The protein expression of genes related to signaling pathway was measured by western blotting. Results of TCGA analysis, qRT-PC and western blotting showed that ISLR was upregulated in colon cancer tumor tissues and cells. High level of ISLR was related to low overall survival of patients with colon cancer. ISLR silence significantly inhibited cell viability, proliferation, migration and invasion of colon cancer cells. ISLR overexpression markedly enhanced the cell viability, proliferation, migration and invasion of colon cancer cells. KEGG database analyzed showed that ISLR can activate the EMT signaling pathway. Inhibition of the EMT signaling pathway can suppress the growth, migration, and invasion of colon cancer cells and eliminate the promoted effect of ISLR overexpression on colon cancer progression. ISLR promotes the progression of colon cancer by activating the EMT signaling pathway.

Tumor Microenvironment: Involved Factors and Signaling Pathways in Epithelial-Mesenchymal Transition

Context: Metastasis is a main cause of death in patients with cancer, whereby tumor cells withdraw from the primary site of the tumor mass and produce secondary tumor mass in new sites. Primary tumor cells depart collectively and individually to invade closed and distant sites. Evidence Acquisition: This review considers TME-derived factors that actuate signaling pathways to induce epithelial-mesenchymal transition (EMT). National Center for Biotechnology Information (NCBI) was the main resource. Google Scholar and Scopus were other databases for finding articles. Keywords that were inserted into the search box of databases to identify related articles were ‘metastasis’, ‘invasion’, ‘epithelial-mesenchymal transition’, ‘EMT’, ‘tumor microenvironment’, ‘TME’, ‘TME cells’, and ‘signaling pathway in EMT’. Titles and abstracts of the articles were studied to choose the right articles. Finally, 107 articles were selected to study in detail and use as references. Results: EMT is a type of metastasis that deprives epithelial single-cells of their characteristic features and acquires mesenchymal features facilitating the departure from the primary tumor mass. During EMT, cell-adhesion and apical-basal polarity rapture and cells obtain movement capability. The tumor microenvironment (TME) leads EMT through secretion factors and signaling pathways. As a result of activating these pathways, transcription factors that abolish epithelial gene expressions and augment mesenchymal gene expression are induced. Conclusions: In this review, recent research published in TME and EMT fields were highlighted and critically appraised. Effect of factors-derived TME cells on EMT were manifested that propose favorite targets for a therapeutic goal to inhibit metastasis. However, data about the effect of the combination of TME cells on metastasis have a small part in the literature.

Role of long noncoding RNA SNHG3 in regulating proliferation, migration and invasion of cervical cancer SiHa cells

To investigate the regulatory role of the long non-coding RNA (lncRNA) small nucleolar host gene 3 (SNHG3) in proliferation, migration and invasion of human cervical cancer cell line SiHa. Array data were retrieved from GEO database to analyze the expression levels of SNHG3 in cervical cancer and adjacent normal tissues. SiHa cells were transfected with a small interfering RNA (siRNA) targeting SNHG3, and the changes in the transcriptional levels of lncRNA SNHG3 and the epithelial-mesenchymal transition (EMT) markers N-cadherin, Snail, vimentin and E-cadherin were detected using real-time quantitative PCR; the protein expressions of N-cadherin, Snail, vimentin and E-cadherin were determined using Western blotting. Cell counting kit-8 (CCK8) assay was utilized to assess the proliferation capacity of the transfected cells. Wound healing assay and Transwell assay were performed to evaluate the transversal and longitudinal migration and invasion abilities of the cells. SNHG3 was over-expressed in cervical cancer tissues and SiHa cells. In SiHa cells, knocking down SNHG3 significantly inhibited the proliferation (P < 0.001), migration (P < 0.01) and invasion abilities (P < 0.001) of the cells, down-regulated the expression levels of N-cadherin, Snail and vimentin (P < 0.001) and up-regulated the expression of E-cadherin (P < 0.001). SNHG3 may promote the proliferation, migration and invasion of SiHa cells by activating the EMT signaling pathway.

Collection on reports of molecules linked to epithelial-mesenchymal transition in the process of treating metastasizing cancer: a narrative review.

Epithelial-mesenchymal transition (EMT) is a morphological process in which epithelial cells transform into mesenchymal cells via a specific procedure. EMT plays an important role in the cancer invasion-metastasis cascade and the current treatment of metastatic cancer, influences the migration, polarity, and adhesion of tumor cells, promotes their migration, invasiveness, anti-apoptotic ability. It contributes to the changes of the tumor microenvironment and suppresses the sensitivity of tumor cells to chemotherapy, causing cancer metastasis and worse, hindering the control and therapy of it. This paper reviews the mechanisms, detection, and treatments of cancer metastasis that have been identified and applied to date, summarizes the EMT-related biological molecules, providing a reference for EMT-targeted research and therapy. As EMT is significant in the progress of tumor metastasis, it is meaningful for the therapy and control of metastatic cancer to understand the mechanism of EMT at the molecular level. We summarized the mechanisms, detection and therapeutic implications of EMT, listed the research progress of molecules like genes, miRNAs, signaling pathways in EMT. We also discussed the prospects of EMT-targeted treatment in cancer metastasis interventions and the challenges the treatment and researches are facing. The summary is conducive to the treatment and further research of EMT and metastatic cancer.

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence worldwide. Late detection and particularly aggressive characteristics are the major challenges that lead to therapeutic failure of this disease. A well described gene program and core regulators are yet to be discovered to drive the metastasis of the PDAC cells. As the development of single cell omics technologies including single cell RNA-sequencing (scRNA-seq), detailed characterization of the cellular composition of solid tumors and their microenvironments are well elaborated. In the current study, we accessed a recently published scRNA-seq dataset on primary and metastatic PDAC tissues and subset the tumor cells. By comparative analysis, we profiled the differentially expressed gene programs of primary and metastatic PDAC and found several long intergenic non-coding RNAs (LincRNAs) in top genes. The PDAC cancer cells showed some heterogeneity and were divided into four major subclusters based on gene profiles, one of which was mostly contributed by metastatic PDAC. Interestingly, this subcluster was remarkably marked by one of the above LincRNAs, MEG3, and exhibited significantly increased Epithelial–Mesenchymal-Transition (EMT) signatures. Ingenuity Pathway Analysis (IPA) on the signature genes of this subcluster gave multiple cancer metastasis associated and EMT signaling pathways, suggesting a critical role of this cluster in leading tumor cell metastasis. Taken together, this study displayed a PDAC cancer subcluster and its marker gene, biologically targeting of which might significantly attenuate the metastasis of tumor and might be a potential strategy for the therapeutic treatment of cancer.

Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing

The epithelial-to-mesenchymal transition (EMT) plays a critical role during normal development and in cancer progression. EMT is induced by various signaling pathways, including TGF-β, BMP, Wnt-β-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-β1 stimulation. Our comprehensive analysis revealed that cells progress through EMT at different paces. Using pseudotime clustering reconstruction of gene-expression profiles during EMT, we found sequential and parallel activation of EMT signaling pathways. We also observed various transitional cellular states during EMT. We identified regulatory signaling nodes that drive EMT with the expression of important microRNAs and transcription factors. Using a random circuit perturbation methodology, we demonstrate that the NOTCH signaling pathway acts as a key driver of TGF-β-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient outcome. Overall, this study provides insight into context-specific drivers of cancer progression and highlights the complexities of the EMT process.

Are We Benign? What Can Wnt Signaling Pathway and Epithelial to Mesenchymal Transition Tell Us about Intracranial Meningioma Progression.

Simple SummaryIntracranial meningiomas are one of the most common primary brain tumors. Although mostly benign, a small portion may exhibit aggressive and malignant characteristics leading to higher recurrence and mortality rate. Detecting the molecular profiles and genes that are involved in meningioma progression can lead to better stratification of patients and more efficient and targeted treatments. The results of this study reveal the role of main actors of the Wnt signaling pathway (β-catenin) and epithelial to mesenchymal transition (E-cadherin, N-cadherin, TWIST1, SNAIL and SLUG) in progression of these tumors, potentially bringing novel biomarkers in diagnostics and molecular targets for therapeutic interventions.Epithelial to mesenchymal transition (EMT), which is characterized by the reduced expression of E-cadherin and increased expression of N-cadherin, plays an important role in the tumor invasion and metastasis. Classical Wnt signaling pathway has a tight link with EMT and it has been shown that nuclear translocation of β-catenin can induce EMT. This research has showed that genes that are involved in cadherin switch, CDH1 and CDH2, play a role in meningioma progression. Increased N-cadherin expression in relation to E-cadherin was recorded. In meningioma, transcription factors SNAIL, SLUG, and TWIST1 demonstrated strong expression in relation to E- and N-cadherin. The expression of SNAIL and SLUG was significantly associated with higher grades (p = 0.001), indicating their role in meningioma progression. Higher grades also recorded an increased expression of total β-catenin followed by an increased expression of its active form (p = 0.000). This research brings the results of genetic and protein analyzes of important molecules that are involved in Wnt and EMT signaling pathways and reveals their role in intracranial meningioma. The results of this study offer guidelines and new markers of progression for future research and reveal new molecular targets of therapeutic interventions.

Identification of Stemness-Related Genes for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma by Integrated Bioinformatics Analysis.

BackgroundInvasion and metastasis of cervical cancer are the main factors affecting the prognosis of patients with cervical squamous cell carcinoma (CESC). Therefore, it is of vital importance to find novel biomarkers that are associated with CESC invasion and metastasis, which will aid in the amelioration of individualized therapeutic methods for advanced patients.MethodsThe gene expression profiles of 10 metastatic and 116 non-metastatic samples were downloaded from The Cancer Genome Atlas (TCGA), where differentially expressed genes (DEGs) were defined. Weighted gene correlation network analysis (WGCNA) was employed to identify the stemness-related genes (SRGs). Univariate and multivariate regression analyses were used to identify the most significant prognostic key genes. Differential expression analysis of transcription factor (TF) and Gene Set Variation Analysis (GSVA) were utilized to explore the potential upstream regulation of TFs and downstream signaling pathways, respectively. Co-expression analysis was performed among significantly enriched TFs, key SRGs, and signaling pathways to construct a metastasis-specific regulation network in CESC. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for the network. Additionally, direct regulatory patterns of key genes were validated by ChIP-seq and ATAC-seq data.ResultsDEGs in yellow module acquired via WGCNA were defined as key genes which were most significantly related to mRNAsi. A multivariate Cox regression model was constructed and then utilized to explore the prognostic value of key SRGs by risk score. Area under curve (AUC) of the receiver operating characteristic (ROC) curve was 0.842. There was an obvious co expression pattern between the TF NR5A2 and the key gene VIM (R = 0.843, p < 0.001), while VIM was also significantly co-expressed with hallmark epithelial mesenchymal transition (EMT) signaling pathway (R = 0.318, p < 0.001). Naringenin was selected as the potential bioactive small molecule inhibitor for metastatic CESC based on CMap analysis.ConclusionsVIM positively regulated by NR5A2 affected EMT signaling pathways in metastatic CESC, and naringenin was the inhibitor for the treatment of metastatic CESC via suppressing cancer stemness. This hypothetical signaling axis and potential inhibitors provide biomarkers and novel therapeutic targets for metastatic CESC.

Circular RNA_0074027 participates in cell proliferation, apoptosis and metastasis of colorectal cancer cells through regulation of miR‑525‑3p.

The present study aimed to elucidate the biological function of circular RNAs (circRNA) 0074027 in colorectal cancer (CRC). The expression of circRNA-0074027 in CRC tissues and cells was determined by reverse transcription-quantitative PCR. The in vitro experiments, including Cell Counting Kit-8 (CCK-8) assay, 5-Ethynyl-2′-deoxyuridine assay, flow cytometry and Transwell assay, were applied to evaluate cell proliferation, apoptosis and metastasis ability respectively following downregulation of circRNA-0074027. The correlation between circRNA-0074027 and micro (mi)RNA-525-3p was determined via dual-luciferase reporter assay. Finally, western blotting was used to explore the possible regulatory mechanism. CircRNA-0074027 was upregulated in CRC tissues, while miR-525-3p expression was reduced. In addition, patients with CRC and circRNA-0074027 overexpression were more likely to have low tumor differentiation, lymph node metastasis and advanced TMN stage. Deletion of circRNA-0074027 could suppress cell proliferation and metastasis through upregulating p53 expression and forbidding epithelial-mesenchymal transition signaling pathway. The addition of miRNA-525-3p inhibitors could reverse the anti-tumor effects induced by the deletion of circRNA-0074027. The downregulation of cirRNA_0074027 inhibited tumor progression via sponging miR-525-3p, which could be a promising treatment bio-marker for CRC.

BDKRB2 is a novel EMT-related biomarker and predicts poor survival in glioma.

Bradykinin receptor B2 (BDKRB2) has been reported as an oncogene in several malignancies. In glioma, the role of BDKRB2 remains unknown. This study aimed at investigating its clinical significance and biological function in glioma at the transcriptional level. We selected 301 glioma patients with microarray data from CGGA database and 697 with RNAseq data from TCGA database. Transcriptome and clinical data of 998 samples were analyzed. Statistical analysis and figure generating were performed with R language. BDKRB2 expression showed a positive correlation with the WHO grade of glioma. BDKRB2 was increased in IDH wildtype and mesenchymal subtype of glioma. Gene ontology analysis demonstrated that BDKRB2 was profoundly associated with extracellular matrix organization in glioma. GSEA analysis revealed that BDKRB2 was particularly correlated with epithelial-to-mesenchymal transition (EMT). GSVA analysis showed that BDKRB2 was significantly paralleled with several EMT signaling pathways, including PI3K/AKT, hypoxia, and TGF-β. Moreover, BDKRB2 expression was significantly correlated with key biomarkers of EMT, especially with N-cadherin, snail, slug, vimentin, TWIST1, and TWIST2. Finally, higher BDKRB2 indicated significantly shorter survival for glioma patients. In conclusion, BDKRB2 was associated with more aggressive phenotypes of gliomas. Furthermore, BDKRB2 was involved in the EMT process and could serve as an independent prognosticator in glioma.