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This study aimed to reveal the potential molecular mechanism associated with thyroid cancer (THCA) prognosis, and investigate promising biomarkers for THCA. Differentially expressed genes (DEGs) were compared between THCA samples (THCA group) and normal samples (N group). Then, enrichment analysis and protein-protein interaction (PPI) network analysis were performed, followed by prognostic hub gene exploration from the PPI network. Furthermore, the prognostic and mutation analysis was performed on these hub genes. Finally, the associations of the hub gene with immune cells were investigated. A total of 802 DEGs were obtained between the THCA group and the N group. These DEGs were mainly enriched in pathways such as lysine degradation. From the PPI network, 20 hub genes, including CD44, CCND1, SNAI1, and KIT, were investigated. The survival analysis showed that the up-regulation of CD44 and down-regulation of SNAI1 contributed to the favorable and unfavorable outcomes of patients with THCA, respectively. Meanwhile, the diagnostic analysis showed that the AUC of KIT in THCA was larger than 0.9. Furthermore, the gene mutation analysis showed that the alternated CCND1 participated in the cell cycle pathway. Finally, the correlation analysis showed that prognostic genes such as CD44 were positively correlated with immune cells such as M1 macrophages. A total of 20 hub genes including CCND1, CD44, SNAI1, and KIT were revealed as potential biomarkers for the differential diagnosis, prognosis, and development of drug targets of THCA. The lysine degradation pathway and cell cycle pathway might take part in the progression of THCA. Show less

To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was used for analysis. Differentially expressed genes were screened with the criteria of false discovery rate<0.05 and l o g 2 F C >1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for differentially expressed genes. Genes encoding transcription factors were further screened for differential expression genes. Then, the expression of these genes during renal fibrosis was verified using unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis model and a public gene expression dataset (GSE104954). After TGF-β1 treatment for 6, 12 and 24 h, 552, 1209 and 1028 differentially expressed genes were identified, respectively. GO analysis indicated that these genes were significantly enriched in development, cell death, and cell migration. KEGG pathway analysis showed that in the early stage of TGF-β1 induction (TGF-β1 treatment for 6 h), the changes in Hippo, TGF-β and Wnt signaling pathways were observed, while in the late stage of TGF-β1 induction (TGF-β1 treatment for 24 h), the changes of extracellular matrix-receptor interaction, focal adhesion and adherens junction were mainly enriched. Among the 291 up-regulated differentially expressed genes treated with TGF-β1 for 6 h, 13 genes ( TGF-β1 induces differentially expressed genes in renal fibroblasts, among which Show less

Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes. Show less

Overexpression of the transmembrane mucin MUC13, as seen in inflammatory bowel diseases (IBD), could potentially impact barrier function. This study aimed to explore how inflammation-induced MUC13 disrupts epithelial barrier integrity by affecting junctional protein expression in IBD, thereby also considering the involvement of MUC1. RNA sequencing and permeability assays were performed using LS513 cells transfected with Show less

Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. We found that NF-PitNET showed an enhanced EMT phenomenon. Show less

Epithelial-Mesenchymal Transition (EMT), triggered by external and internal cues in several physiological and pathological conditions, elicits the transformation of epithelial cells into a mesenchymal-like phenotype. During EMT, epithelial cells lose cell-to-cell contact and acquire unusual motility/invasive capabilities. The associated architectural and functional changes destabilize the epithelial layer consistency, allowing cells to migrate and invade the surrounding tissues. EMT is a critical step in the progression of inflammation and cancer, often sustained by a main driving factor as the transforming growth factor-β1 (TGF-β1). Antagonizing EMT has recently gained momentum as an attractive issue in cancer treatment and metastasis prevention. Herein, we demonstrate the capability of myo-inositol (myo-Ins) to revert the EMT process induced by TGF-β1 on MCF-10A breast cells. Upon TGF-β1 addition, cells underwent a dramatic phenotypic transformation, as witnessed by structural (disappearance of the E-cadherin-β-catenin complexes and the emergence of a mesenchymal shape) and molecular modifications (increase in N-cadherin, Snai1, and vimentin), including the release of increased collagen and fibronectin. However, following myo-Ins, those changes were almost completely reverted. Inositol promotes the reconstitution of E-cadherin-β-catenin complexes, decreasing the expression of genes involved in EMT, while promoting the re-expression of epithelial genes (keratin-18 and E-cadherin). Noticeably, myo-Ins efficiently inhibits the invasiveness and migrating capability of TGF-β1 treated cells, also reducing the release of metalloproteinase (MMP-9) altogether with collagen synthesis, allowing for the re-establishment of appropriate cell-to-cell junctions, ultimately leading the cell layer back towards a more compact state. Inositol effects were nullified by previous treatment with an siRNA construct to inhibit CDH1 transcripts and, hence, E-cadherin synthesis. This finding suggests that the reconstitution of E-cadherin complexes is an irreplaceable step in the inositol-induced reversion of EMT. Overall, such a result advocates for the useful role of myo-Ins in cancer treatment. Show less

As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFβ, potently modify the behavior of healthy stromal cells. A subpopulation of cancer-associated fibroblasts expressing a TGFβ target, the SNAIL1 transcription factor, display myofibroblastic abilities that rearrange the stromal architecture. Breast tumors with the presence of SNAIL1 in the stromal compartment, and with aligned extracellular fiber, are associated with poor survival prognoses. We used deep RNA sequencing and biochemical techniques to study alternative splicing and human tumor databases to test for associations (correlation t-test) between SNAIL1 and fibronectin isoforms. Three-dimensional extracellular matrices generated from fibroblasts were used to study the mechanical properties and actions of the extracellular matrices on tumor cell and fibroblast behaviors. A metastatic mouse model of breast cancer was used to test the action of fibronectin isoforms on lung metastasis. In silico studies showed that SNAIL1 correlates with the expression of the extra domain A (EDA)-containing (EDA+) fibronectin in advanced human breast cancer and other types of epithelial cancers. In TGFβ-activated fibroblasts, alternative splicing of fibronectin as well as of 500 other genes was modified by eliminating SNAIL1. Biochemical analyses demonstrated that SNAIL1 favors the inclusion of the EDA exon by modulating the activity of the SRSF1 splicing factor. Similar to Snai1 knockout fibroblasts, EDA- fibronectin fibroblasts produce an extracellular matrix  that does not sustain TGFβ-induced fiber organization, rigidity, fibroblast activation, or tumor cell invasion. The presence of EDA+ fibronectin changes the action of metalloproteinases on fibronectin fibers. Critically, in an mouse orthotopic breast cancer model, the absence of the fibronectin EDA domain completely prevents lung metastasis. Our results support the requirement of EDA+ fibronectin in the generation of a metastasis permissive stromal architecture in breast cancers and its molecular control by SNAIL1. From a pharmacological point of view, specifically blocking EDA+ fibronectin deposition could be included in studies to reduce the formation of a pro-metastatic environment. Show less

Structural maintenance of chromosomes protein 1 A (SMC1A) is a crucial subunit of the cohesion protein complex and plays a vital role in cell cycle regulation, genomic stability maintenance, chromosome dynamics. Recent studies demonstrated that SMC1A participates in tumorigenesis. This reseach aims to explore the role and the underlying mechanisms of SMC1A in gastric cancer (GC). RT-qPCR and western blot were used to examine the expression levels of SMC1A in GC tissues and cell lines. The role of SMC1A on GC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed. Furthermore,the mechanism of SMC1A action was investigated. SMC1A was highly expressed in GC tissues and cell lines. The high expression of SMC1A indicated the poor overall survival of GC patients from Kaplan-Meier Plotter. Enhancing the expression of SMC1A in AGS cells remarkably promoted cell proliferation in vitro and in vivo, migration and invasion, Conversely, knockdown of SMC1A in HGC27 cells inhibited cell proliferation, migration and invasion. Moreover, it's observed that SMC1A promoted EMT and malignant cell behaviors via regulating SNAIL. Our study revealed that SMC1A promotes EMT process by upregulating SNAIL, which contributes to gastric cancer cell proliferation, migration and invasion. Therefore, targeting SMC1A may be a potential strategy to improve GC therapy. Show less

Tubulin polymerization promoting protein 3 (TPPP3), a member of the tubulin polymerization family, participates in cell progressions in several human cancers, its biological function and the underlying mechanisms in glioblastoma multiforme (GBM) remain unclear. Here, we investigated the role and application value of TPPP3 in gliomas and found that the expression of TPPP3 in glioma was higher than that in normal brain tissue (NBT), and increased with the grade of glioma. Up-regulation of TPPP3 expression in glioblastoma cells confer stronger ability of migration, invasion, proliferation and lower apoptosis in vitro. Inhibition of TPPP3 expression in GBM could reduce the migration, invasion, proliferation and induce the apoptosis of glioblastoma cells. TPPP3 affected the process of EMT by regulating the expression of Snail 1 protein. In clinical data analysis, we found a positive correlation between TPPP3 and Snail1 protein expression levels in glioblastomas. Low TPPP3 expression leads to better survival expectations in glioblastomas patients. The content of this study paves the way for further in-depth exploration of the role of TPPP3 in glioblastoma in the future, and provides new treatment and research directions. Show less

Lung cancer continues to be a major health problem worldwide owing to its incidence, and causes physical, psychological, social, and economic problems. Activated cytotoxic T cells (ACTC) are positively correlated with the tumor microenvironment (TME), improving the prognosis of cancer patients. Recently, ACTC-derived exosomes (ACTC-dExo) were implicated in this effect by inhibiting mesenchymal stem cells, which may promote metastasis in the TME. Exosomes are thought to be advantageous for the specific delivery of drugs to cancer cells because they have the characteristics of natural liposomes, are nanosized, and remain largely stable in the blood due to the protein and lipid content they carry on their membranes. In this study, we aimed to determine the cytotoxic and metastatic inhibitory effects of ACTC-dExo in A549 cells in vitro. Cytotoxic CD8 Show less

Ovarian cancer remains the most lethal gynecologic malignancy in the USA. For over twenty years, epithelial-mesenchymal transition (EMT) has been characterized extensively in development and disease. The dysregulation of this process in cancer has been identified as a mechanism by which epithelial tumors become more aggressive, allowing them to survive and invade distant tissues. This occurs in part due to the increased expression of the EMT transcription factor, Show less

DNAJ heat shock protein family (Hsp40) member C1(DNAJC1) is a member of the DNAJ family. Some members of the DNAJ gene family had oncogenic properties in many cancers. However, the role of DNAJC1 in hepatocellular carcinoma (HCC) was unclear. In this study, expression and prognostic value of DNAJC1 in HCC were analyzed by bioinformatics. Quantitative real-time PCR and Western blotting were used to verify DNAJC1 expression in liver cancer cell lines. Furthermore, immunohistochemical (IHC) was used to detect DNAJC1 expression in liver cancer tissues. Subsequently, the effect of DNAJC1 on the proliferation, migration, invasion and apoptosis of HCC cells was detected by knocking down DNAJC1. Finally, gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of DNAJC1 and was verified by Western blotting. DNAJC1 was highly expressed in HCC and was significantly associated with the prognosis of patients with HCC. Importantly, the proliferation, migration and invasion of Huh7 and MHCC97H cells were inhibited by the knockdown of DNAJC1 and the knockdown of DNAJC1 promoted Huh7 and MHCC97H cell apoptosis. Furthermore, compared to the negative control group, DNAJC1 knockdown in Huh7 and MHCC97H cells promoted the expression of p21, p53, p-p53(Ser20), Bax and E-cadherin proteins, while inhibiting the expression of PARP, MMP9, Vimentin, Snai1, Bcl-2 and N-cadherin proteins. DNAJC1 had a predictive value for the prognosis of HCC. Knockdown of DNAJC1 may inhibit HCC cell proliferation, migration and invasion and promote the HCC cell apoptosis through p53 and EMT signaling pathways. Show less

Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed. Show less

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a hypoxic microenvironment, a high rate of heterogeneity as well as a high likelihood of recurrence. Mounting evidence has affirmed that long non-coding RNAs (lncRNAs) participate in the carcinogenesis of PDAC cells. In this study, we revealed significantly decreased expression of GATA6-AS1 in PDAC based on the GEO dataset and our cohorts, and showed that low GATA6-AS1 expression was linked to unfavorable clinicopathologic characteristics as well as a poor prognosis. Gain- and loss-of-function studies demonstrated that GATA6-AS1 suppressed the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) process of PDAC cells under hypoxia. In vivo data confirm the suppressive roles of GATA6-AS1/SNAI1 in tumor growth and lung metastasis of PDAC. Mechanistically, hypoxia-driven E26 transformation-specific sequence-1 (ETS1), as an upstream modulatory mechanism, was essential for the downregulation of GATA6-AS1 in PDAC cells. GATA6-AS1 inhibited the expression of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) eraser, and repressed SNAI1 mRNA stability in an m6A-dependent manner. Our data suggested that GATA6-AS1 can inhibit PDAC cell proliferation, invasion, migration, EMT process and metastasis under hypoxia, and disrupting the GATA6-AS1/FTO/SNAI1 axis might be a viable therapeutic approach for refractory hypoxic pancreatic cancers. Show less

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths globally. Evidence shows that over 90% of CRC cases are initiated by a deregulated Wingless Integrated Type-1 (WNT)/β-catenin signaling pathway. The WNT/β-catenin pathway also promotes CRC cell proliferation, stemness, and metastasis. Therefore, modulators of the WNT/β-catenin pathway may serve as promising regimens for CRC. This study investigated the effect of cryptolepine-a plant-derived compound-on the WNT/β-catenin pathway in CRC. Two CRC cell lines, COLO205 and DLD1, were treated with cryptolepine or XAV 939 (a WNT inhibitor) in the presence or absence of WNT3a (a WNT activator). Using a tetrazolium-based assay, cryptolepine was found to reduce cell viability in a dose- and time-dependent manner and was a more potent inhibitor of viability than XAV 939. RT-qPCR analyses showed that cryptolepine reverses WNT3a-induced expression of Show less

Colorectal cancer (CRC) is a prevalent cause of cancer and mortality on a global scale. SNAI1, a member of the zinc finger transcription superfamily, is a significant contributor to embryonic development and carcinogenesis through the process of epithelial-mesenchymal transition (EMT). While prior research utilizing CRC cells and clinical data has demonstrated that SNAI1 facilitates CRC progression through diverse mechanisms, the precise manner in which epithelial SNAI1 regulates CRC development in vivo remains unclear. In this study, colitis and colitis-associated CRC were induced through the use of intestinal epithelium-specific Snai1 knockout (Snai1 cKO) mice. Our findings indicate that Snai1 cKO mice exhibit a reduced susceptibility to acute colitis and colitis-associated CRC compared to control mice. Western-blot analysis of colon tissues revealed that Snai1 cKO mice exhibited a higher overall apoptosis level during tumor formation than control mice. No significant differences were observed in the activation of the classical p53 signaling pathway. However, Snai1 cKO mice exhibited weakened EMT and Wnt/β-catenin pathway activation. In summary, our study has provided evidence in vivo that the intestinal epithelial SNAI1 protein suppresses apoptosis, amplifies the EMT, and activates the Wnt/β-catenin signaling pathways in both early and late phases of CRC formation, thus promoting the development and progression of colitis-associated CRC. Show less

Endometrial carcinoma is one of the most common types of cancer among women. The progression of cancer occurs via the Epithelial- Mesenchymal Transition (EMT) pathway. Cells lose their epithelial properties and become mobile. For this reason, the EMT process is one of the most important step to be targeted in cancer treatment. Oleandrin is a cardiac glycoside and its use is limited due to its narrow therapeutic index. In this study, we aimed to evaluate effects of lower level Oleandrin doses on EMT process in endometrial carcinoma. Oleandrin was administrated to Ishikawa endometrial adenocarcinoma cells at different doses and times. IC Show less

Epithelial-mesenchymal transition (EMT) is a process of change in the cellular phenotype from epithelial to mesenchymal morphology. The changes at the cellular level can explain the great heterogeneity and plasticity in the different histological subtypes of gastric carcinomas, which causes difficulties in therapy. In it, epithelial cells reduce intercellular adhesion, which is crucial in the process of invasion and metastasis of gastric carcinomas. Inhibition of cell adhesion molecules such as E-cadherin is known to be influenced by a number of transcription factors, such as Snail and Twist. Show less

Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like 'cold' tumours to CTLA4 blockade. Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells. Show less

Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC. Show less

We have previously shown that the extracellular matrix and basement membrane protein Nidogen1 (NID1) is secreted by more malignant, mesenchymal-like CRC cells and induces the epithelial-mesenchymal transition (EMT) and promotes the migration and invasion of less malignant, epithelial-like CRC cells. Here, we performed a comprehensive bioinformatics analysis of multiple datasets derived from CRC patients and showed that elevated expression of Show less

Glioblastoma (GBM) mesenchymal (MES) transition can be regulated by long non-coding RNAs (lncRNAs) via modulation of various factors (Epithelial-to-Mesenchymal (EMT) markers, biological signalling, and the extracellular matrix (ECM)). However, understanding of these mechanisms in terms of lncRNAs is largely sparse. This review systematically analysed the mechanisms by which lncRNAs influence MES transition in GBM from a systematic search of the literature (using PRISMA) performed in five databases (PubMed, MEDLINE, EMBASE, Scopus, and Web of Science). We identified a total of 62 lncRNAs affiliated with GBM MES transition, of which 52 were upregulated and 10 were downregulated in GBM cells, where 55 lncRNAs were identified to regulate classical EMT markers in GBM (E-cadherin, N-cadherin, and vimentin) and 25 lncRNAs were reported to regulate EMT transcription factors (ZEB1, Snai1, Slug, Twist, and Notch); a total of 16 lncRNAs were found to regulate the associated signalling pathways (Wnt/β-catenin, PI3k/Akt/mTOR, TGFβ, and NF-κB) and 14 lncRNAs were reported to regulate ECM components (MMP2/9, fibronectin, CD44, and integrin-β1). A total of 25 lncRNAs were found dysregulated in clinical samples (TCGA vs. GTEx), of which 17 were upregulated and 8 were downregulated. Gene set enrichment analysis predicted the functions of HOXAS3, H19, HOTTIP, MEG3, DGCR5, and XIST at the transcriptional and translational levels based on their interacting target proteins. Our analysis observed that the MES transition is regulated by complex interplays between the signalling pathways and EMT factors. Nevertheless, further empirical studies are required to elucidate the complexity in this process between these EMT factors and the signalling involved in the GBM MES transition. Show less

Liver fibrosis is the result of the accumulation of extracellular matrix (ECM) that cannot be cleared. Bioinformatic analysis showed that LINC01711 was significantly overexpressed in hepatic fibrosis. The regulatory mechanism of LINC01711 was clarified and confirmed the transcription factors associated with LINC01711. Functionally, LINC01711 promoted LX-2 cell proliferation and migration, indicating that it exerts effects promoting the progression of hepatic fibrosis. Mechanistically, LINC01711 increased the expression of xylosyltransferase 1 (XYLT1), which is an important protein for constructing the ECM. We also confirmed that SNAI1 activated LINC01711 transcription. Taking these findings together, LINC01711 was induced by SNAI1 and promoted the proliferation and migration of LX-2 cells via XYLT1. This study will help to understand the function of LINC01711 and its regulatory mechanism in hepatic fibrosis. Show less

Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial-mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC. Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC. Show less

MicroRNAs (miRNAs) play an essential role in cancer therapy, but the disadvantages of its poor inherent stability, rapid clearance, and low delivery efficiency affect the therapeutic efficiency. Loading miRNAs by nanoformulations can improve their bioavailability and enhance therapeutic efficiency, which is an effective miRNA delivery strategy. In this study, we synthesized layered double hydroxides (LDH), which are widely used as carriers of drugs or genes due to the characteristics of good biocompatibility, high loading capacity, and pH sensitivity. We loaded the suppressor oncogene miR-30a on LDH nanomaterials (LDH@miR-30a) and determined the mass ratio of miRNA binding to LDH by agarose gel electrophoresis. LDH@miR-30a was able to escape the lysosomal pathway and was successfully phagocytosed by breast cancer SKBR3 cells and remained detectable in the cells after 24 h of co-incubation. In vitro experiments showed that LDH@miR-30a-treated SKBR3 cells showed decreased proliferation and cell cycle arrest in the G0/G1 phase and LDH@miR-30a was able to regulate the epithelial-mesenchymal transition (EMT) process and inhibit cell migration and invasion by targeting SNAI1. Meanwhile, in vivo experiments showed that nude mice treated with LDH@miR-30a showed a significant reduction in their solid tumors and no significant impairment of vital organs was observed. In conclusion, LDH@miR-30a is an effective drug delivery system for the treatment of breast cancer. Show less

Breast cancer is the most common cancer among women and the leading cause of cancer-related deaths worldwide. Despite various therapeutic strategies, its impact on the survival rate and quality of life of patients remains limited. The Forkhead Box J3 (FOXJ3) transcription factor has been implicated in various cancers, including lung cancer, tongue squamous cell carcinoma, prostate cancer, and colorectal cancer. However, the role of FOXJ3 in breast cancer has not been elucidated. This study aimed to investigate the role of FOXJ3 in breast cancer development, migration, and invasion. FOXJ3 expression was analyzed in patient tissues and breast cancer cell lines. Loss-of-function and gain-of-function studies were performed using MDA-MB-231 and MCF7 cell lines, respectively. Cell proliferation, migration, and invasion assays were conducted, and the effects of FOXJ3 on Snail expression were examined. FOXJ3 is over-expressed in breast cancer tissues compared to normal counterparts and in various breast cancer cell lines. By modulating FOXJ3 expression in breast cancer cell lines, we observed its influence on cell proliferation, migration, and invasion. Microarray analysis and subsequent validation showed that FOXJ3 modulates Snail expression, a well-known transcription factor involved in epithelial-mesenchymal transition. FOXJ3 plays a role in cell proliferation, migration, and the regulation of Snail expression and may be a potential therapeutic target for breast cancer treatment. Show less

Extravillous trophoblast (EVT) cell invasion is a tightly regulated process that requires for a normal pregnancy. The epithelial-mesenchymal transition (EMT) has been implicated in EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-beta (TGF-β) superfamily, is expressed in the human placenta and promotes EVT cell invasion by upregulating the expression of matrix metalloproteinase 2 (MMP2). However, the underlying molecular mechanism of GDF-8-induced MMP2 expression remains undetermined. Therefore, the present study aims to examine the role of Snail and Slug, the EMT-related transcriptional regulators, in GDF-8-stimulated MMP2 expression and cell invasion in HTR-8/SVneo human EVT cell line and primary cultures of human EVT cells. HTR-8/SVneo and primary cultures of human EVT cells were used to examine the effect of GDF-8 on MMP2 expression and explore the underlying mechanism. For gene silencing and overexpression, the HTR-8/SVneo cell line was used to make the experiments more technically feasible. The cell invasiveness was measured by Matrigel-coated transwell invasion assay. GDF-8 stimulated MMP2 expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effect of GDF-8 on MMP2 expression was blocked by the inhibitor of TGF-β type-I receptors, SB431542. Treatment with GDF-8 upregulated Snail and Slug expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effects of GDF-8 on Snail and Slug expression were blocked by pretreatment of SB431542 and siRNA-mediated knockdown of SMAD4. Interestingly, using the siRNA knockdown approach, our results showed that Snail but not Slug was required for the GDF-8-induced MMP2 expression and cell invasion in HTR-8/SVneo cells. The reduction of MMP2 expression in the placentas with preeclampsia (PE) was also observed. These findings discover the physiological function of GDF-8 in the human placenta and provide important insights into the regulation of MMP2 expression in human EVT cells. Video Abstract. Show less

Cancer cells use the program of epithelial-mesenchymal transition (EMT) for initiation of the invasion-metastasis cascade. Using confocal and video-microscopy, reorganization of the cytoskeleton was studied in the MCF-7 breast cancer cells undergoing Snail1-induced EMT. We used the line of MCF-7 cells stably expressing tetOff SNAI1 construct (MCF-7-SNAI1 cells). After tetracycline washout and Snail1 activation MCF-7-SNAI1 cells underwent EMT and acquired a migratory phenotype while retaining expression of E-cadherin. We identified five variants of the mesenchymal phenotype, differing in cell morphology and migration velocity. Migrating cells had high degree of plasticity, which allowed them to quickly change both the phenotype and migration velocity. The changes of the phenotype of MCF-7-SNAI1 cells are based on the Arp2/3-mediated branched actin network polymerization in lamellipodia, myosin-based contractility in the zone behind the nucleus, redistribution of adhesive proteins from cell-cell contacts to the leading edge, and reorganization of intermediate keratin filaments. Show less