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The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the high co-expression of antisense lncRNAs and adjacent protein-coding genes remains unclear. RNA-seq, CHIP and dual-luciferase reporter assay were performed to identify lncRNAs regulated by SNAI2. MicroRNA-seq and RNA-seq studies were conducted to reveal the biological function of ELF3-AS1 in GC. RNA pulldown and CHIRP assays were conducted to identify the protein that interacts with ELF3-AS1. A total of 123 lncRNAs were identified to be regulated by SNAI2 in GC by RNA sequencing. The ELF3 gene and antisense lncRNA ELF3-AS1 were both transcriptionally repressed by SNAI2 or SNAI1. Down-regulation of ELF3-AS1 and ELF3 predicted poor prognosis in GC. Nuclear localized lncRNA ELF3-AS1 negatively regulated GC cell cycle progression via suppressing G1/S transition and histone synthesis. ELF3-AS1 mainly inhibited GC metastasis by repressing SNAI2 signaling. Additionally, ELF3-AS1 modulated ELF3 mRNA stability by RNA-RNA interaction. The RNA duplexes formed by ELF3 mRNA and lncRNA ELF3-AS1 directly interacted with the double-stranded RNA (dsRNA) binding protein complex ILF2/ILF3 (NF45/NF90). In turn, the ILF2/ILF3 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the dsRNA stability. The SNAI2-ELF3-AS1 feedback loop regulates ELF3 expression at transcriptional and post-transcriptional levels and drives gastric cancer metastasis by maintaining SNAI2 overexpression. The ILF2/ILF3 complex plays a critical role in regulating dsRNA stability. In addition, our work provides a direct evidence that head-to-head antisense lncRNAs can share promoters with neighboring coding genes, which make their expression subject to similar transcriptional regulation, leading to high co-expression. Show less

Lung cancer is one of the top causes of cancer-related death worldwide. Cellular senescence is a characteristic of cell cycle arrest that plays a role in carcinogenesis and immune microenvironment modulation. Despite this, the clinical and immune cell infiltration features of senescence in lung squamous cell carcinoma (LUSC) are unknown. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used to get RNA-seq data and clinical information for LUSC. The least absolute shrinkage and selection operator (LASSO)-Cox regression, receiver operating characteristic (ROC), and Kaplan-Meier analysis were used to evaluate a risk model for predicting overall survival based on six differentially expressed genes. The tumor microenvironment (TME) and immunotherapy response were also studied. To discriminate LUSC into high- and low-risk subgroups, a risk model comprised of six cellular senescence-related genes (CDKN1A, CEBPB, MDH1, SIX1, SNAI1, and SOX5) was developed. The model could stratify patients into high-risk and low-risk groups, according to ROC and Kaplan-Meier analysis. In the TCGA-LUSC and GSE73403 cohorts, the high-risk group had a worse prognosis (P<0.05), and was associated with immune cell inactivation and being insensitive to immunotherapy in IMvigor210. We discovered a new LUSC classification based on six cellular senescence-related genes, which will aid in identifying patients who will benefit from anti-PD-1 treatment. Targeting senescence-related genes appears to be another option for improving clinical therapy for LUSC. Show less

CD73 is an emerging target in cancer due to its role in generating adenosine, a potent immunosuppressor. We found that SNAI1, a driver of epithelial-to-mesenchymal transition (EMT), upregulates CD73 in triple negative breast cancer cells. Here, we discuss the relevance of improving CD73-based therapy by combining with inhibitors of EMT. Show less

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFβ reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney. Show less

Recent studies have identified that circular RNAs (circRNAs) have an important role in cancer via their well-recognized sponge effect on miRNAs, which regulates a large variety of cancer-related genes. However, only a few circRNAs have been well-studied in renal cell carcinoma (RCC) and their regulatory function remains largely elusive. Bioinformatics approaches were used to characterize the differentially expressed circRNAs in our own circRNA-sequencing dataset, as well as two public circRNA microarray datasets. CircNTNG1 (hsa_circ₀₀₀₂₂₈₆₎ was identified as a potential tumor-suppressing circRNA. Transwell assay and CCK-8 assay were used to assess phenotypic changes. RNA pull-down, luciferase reporter assays and FISH experiment were used to confirm the interactions among circNTNG1, miR-19b-3p, and HOXA5 mRNA. GSEA was performed to explore the downstream pathway regulated by HOXA5. Immunoblotting, chromatin immunoprecipitation, and methylated DNA immunoprecipitation were used to study the mechanism of HOXA5. In all three circRNA datasets, circNTNG1, which was frequently deleted in RCC, showed significantly low expression in the tumor group. The basic properties of circNTNG1 were characterized, and phenotype studies also demonstrated the inhibitory effect of circNTNG1 on RCC cell aggressiveness. Clinically, circNTNG1 expression was associated with RCC stage and Fuhrman grade, and it also served as an independent predictive factor for both OS and RFS of RCC patients. Next, the sponge effect of circNTNG1 on miR-19b-3p and the inhibition of HOXA5 by miR-19b-3p were validated. GSEA analysis indicated that HOXA5 could inactivate the epithelial-mesenchymal transition (EMT) process, and this inactivation was mediated by HOXA5-induced SNAI2 (Slug) downregulation. Finally, it was confirmed that the Slug downregulation was caused by HOXA5, along with the DNA methyltransferase DNMT3A, binding to its promoter region and increasing the methylation level. Based on the experimental data, in RCC, circNTNG1/miR-19b-3p/HOXA5 axis can regulate the epigenetic silencing of Slug, thus interfering EMT and metastasis of RCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future study in RCC. Show less

Vasculogenic mimicry (VM) is the process where cancer cells adopt endothelial characteristics by forming tube-like structures and perfusing channels. This phenomenon has been demonstrated in several types of solid tumors and associated with the growth and survival of tumor cells. In this study, we investigated the presence of VM formation in human pancreatic ductal adenocarcinoma (PDAC) and elucidated the molecular mechanisms underlying the VM process. In human PDAC tissues, CD31-negative, periodic acid-Schiff (PAS)-positive channels were predominantly found in desmoplastic areas, which are generally also hypovascularized. We found a positive correlation of VM capacity to tumor size and NOTCH1 expression and nuclear localization with statistical significance, implicating that Notch activity is involved with VM formation. Additionally, our data showed that the presence of growth or angiogenic factors significantly increased Notch activity in PDAC cell lines and upregulated several mesenchymal marker genes, such as TWIST1 and SNAI1, which can be inhibited by a gamma-secretase inhibitor. Our data showed that Notch signaling plays an important role in inducing VM formation in PDAC by promoting the epithelial-to-mesenchymal transition process. Show less

Epithelial-mesenchymal transition (EMT) is involved in the pathophysiology of lung cancer (LC) and COPD, and the latter is an important risk factor for LC. We hypothesised that the EMT gene expression profile and signalling cascade may differ in LC patients with COPD from those with no respiratory diseases. In lung tumour specimens obtained through video-assisted thoracoscopic surgery from LC (n=20, control group) and LC-COPD patients (n=30), gene expression (quantitative real-time PCR amplification) of EMT markers Show less

Prostate cancer (PCa) incidence has increased during the last decades, becoming one of the leading causes of death by cancer in men worldwide. During an extended period of prostate cancer, malignant cells are androgen-sensitive being testosterone the main responsible for tumor growth. Accordingly, treatments blocking production and action of testosterone are mostly used. However, during disease progression, PCa cells become androgen insensitive producing a castration-resistant stage with a worse prognosis. Overcoming castration-resistant prostate cancer (CRPC) has become a great challenge in the management of this disease. In the search for molecular pathways leading to therapy resistance, the epithelial-mesenchymal transition (EMT), and particularly the transcription factors zinc finger E-box-binding homeobox 1 (Zeb1) and zinc finger protein SNAI1 (Snail), master genes of the EMT, have shown to have pivotal roles. Also, the discovery that cancer stem cells (CSCs) can be generated de novo from their non-CSCs counterpart has led to the question whereas these EMT transcription factors could be implicated in this dynamic conversion between non-CSC and CSC. In this review, we analyze evidence supporting the idea that Zeb1 and Snail induce cell malignancy and cancer stem cell phenotype in prostate cells, increasing androgen synthesis capacity and therapy resistance. Show less

While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells (HMLE) with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1 or SNAI1 driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Lastly, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and Aspartic acid recycling. Show less

Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of circulating tumour cell (CTCs) is minimally invasive, can provide real-time information of the heterogeneous tumour and therefore may be a potentially ideal docetaxel response prediction biomarker. In this study we investigate the potential of using CTCs and their gene expression to predict post-docetaxel tumour response, OS and progression free survival (PFS). Peripheral blood was sampled from 18 mCRPC and 43 mHSPC patients, pre-docetaxel treatment, for CTC investigation. CTCs were isolated using the epitope independent Parsortix Detection of CTCs pre-docetaxel was associated with poor patient outcome post-docetaxel treatment. Combining total-CTC number with PSA and ALP predicted lack of partial response (PR) with an AUC of 0.90, p= 0.037 in mCRPC. A significantly shorter median OS was seen in mCRPC patients with positive CTC-score (12.80 vs. 37.33 months, HR= 5.08, p= 0.0005), ≥3 total-CTCs/7.5mL (12.80 vs. 37.33 months, HR= 3.84, p= 0.0053), ≥1 epithelial-CTCs/7.5mL (14.30 vs. 37.33 months, HR= 3.89, p= 0.0041) or epithelial to mesenchymal transitioning (EMTing)-CTCs/7.5mL (11.32 vs. 32.37 months, HR= 6.73, p= 0.0001). Significantly shorter PFS was observed in patients with ≥2 epithelial-CTCs/7.5mL (7.52 vs. 18.83 months, HR= 3.93, p= 0.0058). mHSPC patients with ≥5 CTCs/7.5mL had significantly shorter median OS (24.57 vs undefined months, HR= 4.14, p= 0.0097). In mHSPC patients, expression of While it is clear that CTC numbers and gene expression were prognostic for PCa post-docetaxel treatment, and CTC subtype analysis may have additional value, their potential predictive value for docetaxel chemotherapy response needs to be further investigated in large patient cohorts. Show less

Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during this process. Recent studies have indicated that autophagy is involved in EMT, during which cancer cells depend on autophagy activation for survival. However, accumulating evidence indicates that autophagy's involvement in cancer is context-dependent, acting as either promoter or inhibitor. In this study, we investigated the role of autophagy in supplying energy to support EMT. We induced EMT in Non-small cell lung cancer A549 cells using TGF-β1 with and without autophagy inhibition. Suppression of autophagy activity by knocking down of Show less

Benign prostatic hyperplasia (BPH) is a commonly occurring disease in aging men. It involves cellular proliferation of stromal and glandular tissues leading to prostate enlargement. Current drug therapies show several adverse effects such as sexual dysfunctions and cardiovascular side effects. Therefore, there is a need to develop more effective medical treatment for BPH. In this regard, we aimed to identify genes which play a critical role in BPH. We have obtained the dataset of differentially expressed genes (DEGs) of BPH from NCBI GEO. DEGs were investigated in the context of their protein-protein interactions (PPI). Hub genes i.e. genes associated with BPH were scrutinized based on the topological parameters of the PPI network. These were analyzed for functional annotations, pathway enrichment analysis and transcriptional regulation. In total, 38 hub genes were identified. Hub genes such as transcription factor activator protein-1 and adiponectin were found to play key roles in cellular proliferation and inflammation. Another gene peroxisome proliferator activated receptor gamma was suggested to cause obesity, a common comorbidity of BPH. Moreover, our results indicated an important role of transforming growth factor-beta (TGF-β) signaling and smooth muscle cell proliferation which may be responsible for prostate overgrowth and associated lower urinary tract symptoms frequently encountered in BPH patients. Zinc finger protein Snai1 was the most prominent transcription factor regulating the expression of hub genes that participate in TGF-β signaling. Overall, our study has revealed significant hub genes that can be employed as drug targets to develop potential therapeutic interventions to treat BPH. Show less

Glioblastoma multiforme (GBM), which is a malignant primary brain tumor, is the cancer that spreads most aggressively into the adjacent brain tissue. Patients with metastatic GBM have a poor chance of survival. In this study, we examined the anti-GBM mobility effect of small protein, called GMI, which is cloned and purified from Ganoderma microsporum. Proteomic profiles showed that GMI-mediated proteins were involved in cell motility and cell growth functions. Specifically, we demonstrated that GMI significantly suppressed cell migration and invasion of GBM cells. GMI combined with temozolomide (TMZ), which is a traditional chemotherapeutic agent for GBM treatment, synergistically inhibited motility in GBM cells. Mechanistically, we demonstrated that GMI induced proteasome-dependent degradation of Slug, which is a critical transcription factor, is frequently linked to metastasis and drug resistance in GBM. Knockdown of Slug reduced cell viability and colony formation of GBM cells but enhanced TMZ-suppressed cell migration and viability. The results of this study show that targeting Slug degradation is involved in GMI-suppressed mobility of GBM cells. Moreover, GMI may be a potential supplementary agent for the suppression of GBM. Show less

The preservation of the chondrogenic phenotype and hypoxia-related physiological microenvironment are major challenges in the 2D culture of primary human chondrocytes. To address this problem, we develop a 3D culture system generating scaffold-free spheroids from human chondrocytes. Our results highlight the chondrogenic potential of cultured human articular chondrocytes in a 3D system combined with hypoxia independently of the cartilage source. After 14 days of culture, we developed spheroids with homogenous diameter and shape from hyaline cartilage donors. Spheroids generated in hypoxia showed a significantly increased glycosaminoglycans synthesis and up-regulated the expression of Show less

Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. The expression levels of TGF-β signaling genes ( The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis. Show less

Ionizing radiation (IR) is one of the major therapeutic approaches in the non-small cell lung cancer (NSCLC); however, it can paradoxically result in cancer progression likely through promoting epithelial-mesenchymal transition (EMT) and the cancer stem cell phenotype. Therefore, we aimed to determine whether IR promote EMT/CSC and to investigate the clinical relevance of EMT/CSC hallmark genes. In this experimental and bioinformatic study, A549 cell line was irradiated with a high dosage (6 Gy) or a fractionated regimen (2 Gy/day for 15 fractions). The EMT-related features, including cellular morphology, migratory and invasive capacities were evaluated using scratch assay and transwell migration/invasion assays. The mRNA levels of EMT-related genes ( Irradiation resulted in a dramatic elongation of cell shape and enhanced invasion and migration capabilities. These EMT-like alterations were accompanied with enhanced levels of Altogether, these findings demonstrated that IR promotes EMT phenotype and stem cell markers in A549 cell line and these genes could function as diagnostic or prognostic indicators in LUAD samples. Show less

The bacteriocin, nisin, produced by Lactococcus and Streptococcus species during fermentation, is widely used for bio preservatives in a wide variety of foods. Liver cancer has a high mortality rate and is the fourth leading cause of cancer-related deaths worldwide. Recently, researchers have shown the anti-cancer effects of nisin through in vitro and in vivo studies. This study aimed to investigate the effect of nisin on liver cancer cell lines, which represented two subgroups of the disease model. Nisin exhibited significant growth inhibition and apoptosis in both cell lines, HuH-7, and SNU182. Drug resistance is the main problem in liver cancer and the epithelial-to-mesenchymal transition has a role in the development of drug resistance in hepatocellular carcinoma. The expression of EMT transcription factors ZEB1, SNAI1, and TWIST1 were analyzed depending on nisin treatment, TWIST1 expression was down-regulated after nisin treatment compared to the untreated SNU182 and HuH-7 cell lines. Besides, due to the reported correlation between the overexpression of Frizzled (FZD) proteins, specifically FZD7, in primary hepatocellular carcinomas (HCCs), molecular docking was assessed for Nisin A in the binding site of FZD7. Results confirmed that Nisin A was able to form important hydrogen bonding with key residues. This research not only determined the role of nisin in different liver cancer cell models but it also provided the first result of FZD7 and nisin interaction. Show less

Previously, we reported that heterologous expression of an embryonic transcription factor, Tbx18, reprograms ventricular cardiomyocytes into induced pacemaker cells (Tbx18-iPMs), though the key pathways are unknown. Here, we have used a tandem mass tag proteomic approach to characterize the impact of Tbx18 on neonatal rat ventricular myocytes. Tbx18 expression triggered vast proteome remodeling. Tbx18-iPMs exhibited increased expression of known pacemaker ion channels, including Hcn4 and Cx45 as well as upregulation of the mechanosensitive ion channels Piezo1, Trpp2 (PKD2), and TrpM7. Metabolic pathways were broadly downregulated, as were ion channels associated with ventricular excitation-contraction coupling. Tbx18-iPMs also exhibited extensive intracellular cytoskeletal and extracellular matrix remodeling, including 96 differentially expressed proteins associated with the epithelial-to-mesenchymal transition (EMT). RNAseq extended coverage of low abundance transcription factors, revealing upregulation of EMT-inducing Snai1, Snai2, Twist1, Twist2, and Zeb2. Finally, network diffusion mapping of >200 transcriptional regulators indicates EMT and heart development factors occupy adjacent network neighborhoods downstream of Tbx18 but upstream of metabolic control factors. In conclusion, transdifferentiation of cardiac myocytes into pacemaker cells entails massive electrogenic, metabolic, and cytostructural remodeling. Structural changes exhibit hallmarks of the EMT. The results aid ongoing efforts to maximize the yield and phenotypic stability of engineered biological pacemakers. Show less

The transcription factor SNAI1 mediates epithelial-mesenchymal transition, fibroblast activation and controls inter-tissue migration. High SNAI1 expression characterizes metastatic triple-negative breast carcinomas, and its knockout by CRISPR/Cas9 uncovered an epithelio-mesenchymal phenotype accompanied by reduced signaling by the cytokine TGFβ. The SNAI1 knockout cells exhibited plasticity in differentiation, drifting towards the luminal phenotype, gained stemness potential and could differentiate into acinar mammospheres in 3D culture. Loss of SNAI1 de-repressed the transcription factor FOXA1, a pioneering factor of mammary luminal progenitors. FOXA1 induced a specific gene program, including the androgen receptor (AR). Inhibiting AR via a specific antagonist regenerated the basal phenotype and blocked acinar differentiation. Thus, loss of SNAI1 in the context of triple-negative breast carcinoma cells promotes an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the dual transcriptional action of FOXA1 and AR. This function of SNAI1 provides means to separate cell invasiveness from progenitor cell de-differentiation as independent cellular programs. Show less

Distant metastasis is the major cause of clear cell renal cell carcinoma (ccRCC)-associated mortality. However, molecular mechanisms involved in ccRCC metastasis remain to be fully understood. With the increasing appreciation of the role of long non-coding RNAs (lncRNAs) in cancer development, progression, and treatment resistance, the list of aberrantly expressed lncRNAs contributing to ccRCC pathogenesis is expanding rapidly. Bioinformatics analysis was carried out to interrogate publicly available ccRCC datasets. In situ hybridization and qRT-PCR assays were used to test lncRNA expression in human ccRCC tissues and cell lines, respectively. Chromatin immunoprecipitation and luciferase reporter assays were used to examine transcriptional regulation of gene expression. Wound healing as well as transwell migration and invasion assays were employed to monitor ccRCC cell migration and invasion in vitro. ccRCC metastasis was also examined using mouse models in vivo. RNA pulldown and RNA immunoprecipitation were performed to test RNA-protein associations, whereas RNA-RNA interactions were tested using domain-specific chromatin isolation by RNA purification. MILIP expression was upregulated in metastatic compared with primary ccRCC tissues. The increased MILIP expression in metastatic ccRCC cells was driven by the transcription factor AP-2 gamma (TFAP2C). Knockdown of MILIP diminished the potential of ccRCC cell migration and invasion in vitro and reduced the formation of ccRCC metastatic lesions in vivo. The effect of MILIP on ccRCC cells was associated with alterations in the expression of epithelial-to-mesenchymal transition (EMT) hallmark genes. Mechanistically, MILIP formed an RNA-RNA duplex with the snail family transcriptional repressor 1 (Snai1) mRNA and bound to Y-box binding protein 1 (YBX1). This promoted the association between the YBX1 protein and the Snai1 mRNA, leading to increased translation of the latter. Snai1 in turn played an important role in MILIP-driven ccRCC metastasis. The TFAP2C-responsive lncRNA MILIP drives ccRCC metastasis. Targeting MILIP may thus represent a potential avenue for ccRCC treatment. Show less

The pro-inflammatory factor interleukin-8 (IL-8) is related to poor prognosis in hepatocellular carcinoma (HCC) patients. Interleukin-8 enhanced HCC invasion by upregulating Snail and Twist1, whether this modulation relies on microRNAs (miR) is unclear. In this study, hsa-miR-370-3p was screened as candidate miRNA targeting Snail and Twist1, and its expression was downregulated by IL-8. Luciferase assays and RNA electrophoretic mobility shift assays were used to evaluate the interaction between miR-370-3p and targeted mRNAs. Coimmunoprecipitation, luciferase, and ChIP assays were undertaken to investigate the mechanisms underlying IL-8-mediated modification of miR-370-3p. Gain- and loss-of-function studies, Transwell assays, and a xenograft nude mouse model were used to investigate pro- and antitumor activities. Interleukin-8 and miR-370-3p levels were analyzed for clinical relevance in HCC patients. Our results showed that HCC patients with high levels of IL-8 experienced more metastasis and shorter survival. Interleukin-8 induced epithelial-mesenchymal transition and promoted liver cancer cell migration, invasion, and metastasis both in vitro and in vivo. MicroRNA-370-3p interacted with its cognate mRNA within the 3'-UTR regions of Twist1 and Snail mRNA directly and specifically and attenuated IL-8 protumoral effects on liver cancer cells. Interleukin-8 negatively modulated miR-370-3p through signal transducer and activator of transcription 3 (STAT3) activation by recruiting histone deacetylase 1 (HDAC1) to miR-370-3p promoter. The STAT3 and HDAC antagonists inhibited liver cancer cell migration and invasion. Patients with high miR-370-3p and low IL-8 levels had longer overall survival. In conclusion, our study elucidated a novel axis IL-8/STAT3/miR-370-3p/Twist1 and Snail relying on HDAC1 recruitment, which showed both diagnostic and therapeutic potentials of miR-370-3p in HCC metastasis. Show less

While most cases of cutaneous squamous cell carcinoma (cSCC) are benign, invasive cSCC is associated with higher mortality and is often more difficult to treat. As such, understanding the factors that influence the progression of cSCC are important. Aggressive cancers metastasize through a series of evolutionary changes, collectively called the epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells transition to a highly mobile mesenchymal cell type with metastatic capacities. While changes in expression of TGF-β, ZEB1, SNAI1, MMPs, vimentin, and E-cadherin are hallmarks of an EMT process occurring within cancer cells, including cSCC cells, EMT within tissues is not an "all or none" process. Using patient-derived cSCC and adjacent normal tissues, we show that cells within individual cSCC tumors are undergoing a hybrid EMT process, where there is variation in expression of EMT markers by cells within a tumor mass that may be facilitating invasion. Interestingly, cells along the outer edges of a tumor mass exhibit a more mesenchymal phenotype, with reduced E-cadherin, β-catenin, and cytokeratin expression and increased vimentin expression. Conversely, cells in the center of a tumor mass retain a higher expression of the epithelial markers E-cadherin and cytokeratin and little to no expression of vimentin, a mesenchymal marker. We also detected inverse expression changes in the miR-200 family and the EMT-associated transcription factors ZEB1 and SNAI1, suggesting that cSCC EMT dynamics are regulated in a miRNA-dependent manner. These novel findings in cSCC tumors provide evidence of phenotypic plasticity of the EMT process occurring within patient tissues, and extend the characterization of a hybrid EMT program occurring within a tumor mass. This hybrid EMT program may be promoting both survival and invasiveness of the tumors. A better understanding of this hybrid EMT process may influence therapeutic strategies in more invasive disease. Show less

In recent years, peri-organ fat has emerged as a diagnostic and therapeutic target in metabolic diseases, including diabetes mellitus. Here, we performed a comprehensive analysis of epicardial adipose tissue (EAT) transcriptome expression differences between diabetic and non-diabetic participants and explored the possible mechanisms using various bioinformatic tools. RNA-seq datasets GSE108971 and GSE179455 for EAT between diabetic and non-diabetic patients were obtained from the public functional genomics database Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were identified using the R package DESeq2, then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed. Next, a PPI (protein-protein interaction) network was constructed, and hub genes were mined using STRING and Cytoscape. Additionally, CIBERSORT was used to analyze the immune cell infiltration, and key transcription factors were predicted based on ChEA3. By comparing EAT samples between diabetic and non-diabetic patients, a total of 238 DEGs were identified, including 161 upregulated genes and 77 downregulated genes. A total of 10 genes (IL-1β, CD274, PDCD1, ITGAX, PRDM1, LAG3, TNFRSF18, CCL20, IL1RN, and SPP1) were selected as hub genes. GO and KEGG analysis showed that DEGs were mainly enriched in the inflammatory response and cytokine activity. Immune cell infiltration analysis indicated that macrophage M2 and T cells CD4 memory resting accounted for the largest proportion of these immune cells. CSRNP1, RELB, NFKB2, SNAI1, and FOSB were detected as potential transcription factors. Comprehensive bioinformatic analysis was used to compare the difference in EAT between diabetic and non-diabetic patients. Several hub genes, transcription factors, and immune cell infiltration were identified. Diabetic EAT is significantly different in the inflammatory response and cytokine activity. These findings may provide new targets for the diagnosis and treatment of diabetes, as well as reduce potential cardiovascular complications in diabetic patients through EAT modification. Show less

Compared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed. Tumor-derived exosomes were purified by differential ultracentrifugation and validated by nanoparticle tracking analysis and transmission electron microscopy. A proximity ligation assay and interleukin-1β (IL-1β) level were used for detecting activation of NLRP3 inflammasomes. RNA sequencing was used to analyze the exosomal RNAs. We demonstrated that in cancer cells undergoing Snail-induced epithelial-mesenchymal transition (EMT), tumor cells suppress NLRP3 inflammasome activities of tumor-associated macrophages (TAMs) in response to chemotherapy through the delivery of exosomal miR-21. Mechanistically, miR-21 represses This finding reveals the mechanism of EMT-mediated resistance beyond cancer stemness through modulation of post-treatment inflammasome activity. It also highlights the dynamic remodeling of the TME throughout metastatic evolution. Show less

The epithelial to mesenchymal transition (EMT) is crucial for cancer progression and chemoresistance. EMT is a dynamic process with multiple phases that change cell migration and invasion activity. We used pan-cancer expression data to find 14-LncRNAs that had a high correlation with the EMT markers VIM, CDH1, FN1, SNAI1, and SNAI2. The expression of 14 EMT-associated LncRNA, which also showed high cancer specificity, was used to calculate the pan-cancer EMT score. The EMT score was then applied to the 32 cancer types to classify them as epithelial, epithelial-mesenchymal, mesenchymal-epithelial, or mesenchymal tumors. We discovered that the EMT score is a poor prognostic predictor and that as tumor mesenchymal nature increased, patient survival decreased. We also showed that the cell of origin did not influence the EMT nature of tumors. Pathway analysis employing protein expression data revealed that the PI3K pathway is the most crucial in determining the EMTness of tumors. Further, we divided CCLE-cell lines into EMT classes and discovered that mesenchymal cells, which exhibited higher PI3K pathway activation, were more sensitive to PI3K inhibitors than epithelial cells. We identified Linc01615 as a mesenchymal LncRNA whose expression significantly correlated with survival in several cancer types. We showed that Linc01615 is regulated by the TGFβ-STAT3 pathway in a feedback loop. Knockdown of Linc01615 inhibited cell proliferation and migration by regulating the PI3K pathway and mesenchymal markers. We also identified RP4-568C11.4 as an epithelial cancer marker. We showed that knocking down RP4-568C11.4 decreased cell growth but not migration. In addition, we discovered that ESR1 regulates RP4-5681C11.4 in breast cancer. Taken together, we have developed a pan-cancer EMT signature. Also, we found two new LncRNAs that have different effects on cancer development and EMT. Show less

The current study aimed to determine crucial genes targeted by toxin-A through network analysis. The significant differentially expressed genes (DEGs) of human intestinal Caco-2 cells treated by toxin-A versus control were retrieved from gene expression omnibus (GEO). The queried DEGs were analyzed using by protein-protein interaction (PPI) network analysis through STRING database and Cytoscape software v.3.7.2. Among 157 significant DEGs, JUN, VEGFA, CDKN1A, ATF3, SNAI1, DUSP1, HSPB1, MCL1, KLF4, FOSL1, HSPA1A, and SQSTM1 were determined as hubs and JUN, DUSP1, DUSP5, EZR, MAP1LC3B, and SQSTM1 were highlighted as bottlenecks. JUN, DUSP1, and SQSTM1 are possible drug targets to prevent and treat Show less

Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-β (TGF-β) signaling is a powerful regulator to promote metastasis of LUAD. Here, we screened long non-coding RNAs (lncRNAs) responsive to TGF-β and highly expressed in LUAD cells, and finally obtained our master molecular LINC00152. We proved that the TGF-β promoted transcription of LINC00152 through the classical TGF-β/SMAD3 signaling pathway and maintained its stability through the RNA-binding protein HuR. Moreover, LINC00152 increased ZEB1, SNAI1 and SNAI2 expression via increasing the interactions of HuR and these transcription factors, ultimately promoting epithelial-mesenchymal transition of LUAD cell and enhancing LUAD metastasis in vivo. These data provided evidence that LINC00152 induced by TGF-β promotes metastasis depending HuR in lung adenocarcinoma. Designing targeting LINC00152 and HuR inhibitors may therefore be an effective therapeutic strategy for LUAD treatment. Show less