Limiting serum concentration in culture medium constitutes an environmental stress that disrupts cellular homeostasis and activates adaptive metabolism. This study aims to examine the impact of dexamethasone (DEX) on biological properties (e.g. viability, adhesion, migration) and glucose and lipid metabolism of prostate epithelial cells under stress conditions. The study used a non-tumorigenic human prostate cell line, PNT1A. In mild serum deprivation conditions, DEX, commonly used in the treatment of castration-resistant prostate cancer, also arrests normal prostate cells in the G0/G1 phase. Observed reduction in metabolic activity and limiting apoptosis of PNT1A cells as related to decreased expression of the NF-κB family and FOXO3 genes. Moreover, DEX modulated PNT1A migration by regulating cell plasticity thought capacity of adhesion to ECM proteins such as fibronectin and collagen I and IV. This was associated with changes in mRNA levels for the genes VIM, ZEB1 and ZEB2. Finally, it seems that dexamethasone helps PNT1A cells adapt to stress and enhance antioxidant defense, possibly by reprogramming lipid metabolism (e.g., LDLR, CPT1, MGLL), but not necessarily glucose metabolism.

The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors.

The active vitamin D-degrading enzyme (CYP24A1) is commonly overexpressed in various types of cancer, which is associated with poor prognosis in cancer patients. Recent studies highlight the antagonism of CYP24A1 toward the anticancer role of active vitamin D. However, the impact of CYP24A1 on tumorigenesis and its underlying mechanisms largely remains unexplored. This study also found that high CYP24A1 mRNA expressions were associated with poor prognosis in ovarian cancer and lung adenocarcinoma (LUAD) patients. Moreover, we demonstrated that the overexpression of CYP24A1 accelerated the proliferation, migration, and invasion of ovarian cancer and LUAD cancer cells in vitro. Furthermore, knockdown of CYP24A1 displayed an anticancer effector both in vitro and in vivo. Mechanically, 87-297 amino acid motif of CYP24A1 bound specifically to FUS protein, consequentially reducing FUS affinity for miR-200c. Considering FUS promotes gene silencing by binding to microRNA targets, a decrease in miR-200c levels led to a notable activation of its target ZEB1, resulting in the promotion of the epithelial-mesenchymal transition (EMT) process. In conclusion, FUS binding specifically by CYP24A1 impaired miR-200c-mediated ZEB1 silencing, thereby augmenting EMT progression and tumorigenesis. These findings elucidate a fundamental mechanism by which CYP24A1 operates as an oncogene, offering potential targets for therapeutic interventions in cancer treatment.

Glycosylation, a major posttranslational modification (PTM), is often dysregulated in cancer due to altered glycosyltransferase activity. Studies have shown specific changes in glycan structures associated with epithelial-mesenchymal transition (EMT) in cancer cells. However, the specific mechanism by which glycosyltransferases contribute to EMT remains unclear. In this study, we used bronchoalveolar lavage fluid (BALF) from lung adenocarcinoma (LUAD) patients to comparatively characterize glycopatterns and identify dysregulated glycosyltransferases in LUAD. We found a significant reduction in N-glycans containing the bisecting GlcNAc structure and confirmed by Western blot that N-acetylglucosaminyltransferase-III (MGAT3) is downregulated in LUAD. We observed a notable downregulation of both messenger RNA (mRNA) and protein expression of Forkhead box protein A2 (FOXA2) in early-stage LUAD, with FOXA2 loss emerging as an EMT promoter. Interestingly, cellular EMT models demonstrated that FOXA2 deficiency decreased MGAT3 expression during TGF-β1-driven EMT, leading to reduced levels of bisecting-GlcNAc N-glycans in LUAD cells. Our findings unveil a novel mechanism underlying the downregulation of MGAT3 and bisecting GlcNAc N-glycan expression during EMT, a process crucial for tumor metastasis.

Ocular trauma and surgery are considered the most common cause for proliferative vitreoretinopathy (PVR). Many retinal cell types are thought to be the cellular source for PVR although most risk factors for PVR are associated with intravitreal dispersion of the retinal pigment epithelium (RPE) cells. Major PVR animal models are rabbit and swine with an artificial implantation of exogenous cells into the vitreous to form epiretinal membrane (ERM) which does not recapitulate a real PVR pathology. To clarify and validate the participation of RPE cells, to mimic ocular trauma in situ, and to reveal the related macromolecule changes in PVR pathology, we utilized a dispase treatment to damage the retina in establishment of a reliable RPE-tagged PVR mouse model with ERM-like tissues formed within and on both surface of the retina. The immunostaining of patient epiretinal membranes with lineage markers confirms RPE is involved in PVR development. Quantitative PCR analysis indicates the dedifferentiation of RPE cells switches RPE from epithelial to mesenchymal phenotype to re-enter a proliferative and mobile state underlying PVR. Gene expression results of the mouse PVR model retinas are consistent with the microarray gene expression profile of human PVR retinas, validating that our mouse PVR model resembles human PVR and is thereby suitable for molecular mechanism and pharmaceutical studies.

Radiation therapy (RT) is fundamental to the fight against cancer because of its exceptional ability to target and destroy cancer cells. However, conventional radiation therapy can significantly affect the adjacent normal tissues, leading to fibrosis, inflammation, and decreased organ function. This tissue damage not only reduces the quality of life but also prevents the total elimination of cancer. The transformation of epithelial cells into mesenchymal-like cells, termed epithelial-mesenchymal transition (EMT), is essential for processes such as fibrosis, embryogenesis, and wound healing. Conventional radiation therapy increases the asymmetric activation of fibrotic and inflammatory pathways, and the resulting chronic fibrotic changes and organ dysfunction are linked to radiation-induced epithelial-mesenchymal transition. Recent advances in radiation therapy, namely flash radiation therapy (FLASH-RT), have the potential to widen the therapeutic index. Radiation delivered by FLASH-RT at very high dose rates (exceeding 40 Gy/s) can protect normal tissue from radiation-induced damage, a phenomenon referred to as the "FLASH effect". Preclinical studies have demonstrated that FLASH-RT successfully inhibits processes associated with fibrosis and epithelial-mesenchymal transition, mitigates damage to normal tissue, and enhances regeneration. Three distinct types of EMT have been identified: type-1, associated with embryogenesis; Type-2, associated with injury potential; and type-3, related with cancer spread. The regulation of EMT via pathways, including TGF-β/SMAD, WNT/β-catenin, and NF-κB, is essential for radiation-induced tissue remodelling. This study examined radiation-induced EMT, TGF-β activity, multiple signalling pathways in fibrosis, and the potential of FLASH-RT to reduce tissue damage. FLASH-RT is a novel approach to treat chronic tissue injury and fibrosis post-irradiation by maintaining epithelial properties and regulating mesenchymal markers including vimentin and N-cadherin. Understanding these pathways will facilitate the development of future therapies that can alleviate fibrosis, improve the efficacy of cancer therapy, and improve the quality of life of patients.

The epithelial mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and adhesion characteristics, and adopt a mesenchymal phenotype. While the EMT naturally occurs during tissue fibrosis, wound healing, and embryonic development, it can be exploited by cancer cells and is strongly associated with cancer stem cell formation, tissue invasiveness, apoptosis, and therapy resistance. Transcription factors (TFs) such as SNAIL, ZEB, and TWIST play a pivotal role in driving the EMT. This systematic review aims to assess the impact of EMT-TFs on hematological malignancy and solid tumors.

English-language literature published between 2010 and 2024 was systematically reviewed, utilizing databases such as PubMed and Google Scholar.

A total of 3250 studies were extracted. Of these, 92 publications meeting the inclusion criteria were analyzed to elucidate the role of EMT-TFs in cancer. The results demonstrated that the EMT-TFs play a critical role in both hematological and solid tumor development and progression. They promote invasive, migratory, and metastatic properties in these tumors, and contribute to therapeutic challenges by enhancing chemoresistance. A strong correlation between EMT-TFs and poor overall survival has been identified.

Our research concluded that EMT-TFs may serve as important predictive and prognostic factors, as well as potential therapeutic targets to mitigate cancer progression.

Tripartite motif-containing protein 50 (TRIM50) is a recently discovered E3 ubiquitin ligase that participates in tumor progression. TRIM50 is overexpressed in many cancers, although few studies focused on TRIM50's role in breast cancer.

We overexpressed TRIM50 in triple-negative breast cancer cell lines using plasmid and found that TRIM50 upregulation markedly reduced breast cancer cell proliferation, clone formation, and migration, as well as promoted breast cancer cell apoptosis. Western blotting revealed that accumulated TRIM50 resulted in both mRNA and protein depletion of SNAI1, and partially attenuated the epithelial-mesenchymal transition (EMT) induced by SNAI1.

In this study, we demonstrate that TRIM50 is downregulated in human breast cancer and that its overexpression closely correlates with diminished invasion capacity in breast cancer, suggesting that TRIM50 may serve as a diagnostic marker and therapeutic target.

TRIM50 plays a key role in breast cancer proliferation and potentially serves as a prognostic and therapeutic target.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in cancer progression. We found lncRNA DNM1P35 is elevated in ovarian tumors compared to normal tissues, and demonstrated that lncRNA DNM1P35 promoted cancer cell proliferation, migration and invasion in SK-OV-3 and OVCAR-3 cell lines. Furthermore, lncRNA DNM1P35 also facilitated the epithelial-mesenchymal transition (EMT) of ovarian cancer cells. Mechanistic studies identified microRNA-326 (miR-326) as a target of lncRNA DNM1P35. Overexpression of miR-326 diminished the tumor-promoting activity of lncRNA DNM1P35, resulting in reduction of Zinc finger E-box-binding homeobox 1 (ZEB1) expression and EMT features. We further revealed that ZEB1, a master transcription factor for EMT that is negatively regulated by miR-326, was essential for lncRNA DNM1P35-mediated cancer cell progression and EMT. Loss of ZEB1 led to compromised pro-tumoral activity of lncRNA DNM1P35. In vivo studies using a xenograft mouse model of ovarian cancer revealed that tumors with higher levels of lncRNA DNM1P35 led to shorter survival, increased tumor burden, as well as elevated expression of proliferative marker Ki67 and EMT marker ZEB1. Our comprehensive study underscored the significance of lncRNA DNM1P35 in ovarian cancer progression, elucidating the underlying mechanism through miR-326/ZEB1 axis to promote ovarian cancer progression.

Metastatic castration-resistant prostate cancer is the most dangerous stage of prostate cancer, with a high mortality rate. Docetaxel chemotherapy is one of the most effective treatment methods currently, but some patients do not respond to chemotherapy. To avoid unnecessary toxicity in non-responders, this study explores the potential of circulating microRNAs as early biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer.

PC3 cells and DU145 cells were divided into the control, NC mimics, and miRNA-136-5p-mimics groups. Cell viability was measured using the CCK-8 assay. Cell apoptosis was determined by flow cytometry. Cell migration and invasion abilities were evaluated using the Transwell assay. Real-time quantitative PCR was used to measure the miRNA levels in cells and peripheral blood of patients. The miRNA-136-5p target genes were predicted by using the PITA, TargetScan, and miRanda databases. The target genes were analyzed with KEGG pathway analysis.

In both PC3 and DU145 cells, the miRNA-136-5p-mimics group exhibited significantly increased cell survival rates, migration and invasion numbers, and significantly decreased apoptosis rates than the control group (p < 0.05). The miRNA-222-3p and miRNA-136-5p levels were significantly increased in docetaxel-resistant PC3 and DU145 cells (p < 0.05). The levels of circulating miRNA-222-3p and miRNA-136-5p were significantly associated with docetaxel treatment (p < 0.05). Higher levels of miRNA-222-3p were observed in non-responsive patients (p < 0.05). The area under the curve for miRNA-222-3p was 0.76 (95%CI: 0.55-0.97), indicating its effectiveness as a predictive factor for non-responsive patients to docetaxel. Patients with high expression of miRNA-34c-5p after docetaxel chemotherapy had shorter overall survival times (P < 0.05). Bioinformatics analysis identified 110 potential target genes of miRNA-136-5p. KEGG revealed that these genes were mainly distributed in three pathways. Among them, the PI3K-AKT pathway was closely related to the metastasis of prostate cancer cells.

Our study demonstrates that miRNA-136-5p promotes the proliferation and invasion of PC3 and DU145 cells while inhibiting apoptosis. Circulating miRNA-222-3p may serve as a biomarker for early therapeutic response to docetaxel, and further clinical investigation is warranted. Additionally, miRNA-136-5p may have anti-cancer effects during docetaxel chemotherapy in metastatic castration-resistant prostate cancer.

Epithelial to mesenchymal transition (EMT) has been shown to play an essential role in the early stages of cancer cell invasion and metastasis. Inducible EMT models can initiate EMT in a controlled manner, thereby providing the opportunity to determine whether a cancer-associated gene influences cancer metastasis by triggering EMT. Moreover, different inducible EMT models enable the investigation of specific mechanisms of EMT modulation by various genes, facilitating a more precise understanding of how these genes influence cancer metastasis through the induction of EMT. Unfortunately, current inducible EMT models still present unmet needs. Therefore, we aimed to establish an inducible EMT model in MCF10A cells, a spontaneously immortalized human fibrocystic mammary cell line, by manipulating the expression of mouse Twist1 (mTwist1). In this study, we first compared the EMT induction capacity between human TWIST1 (hTWIST1) and mTwist1, and selected mTwist1 for further investigation. By monitoring the changes in epithelial and mesenchymal markers at different induction time points, we examined the EMT process in both polyclonal and monoclonal MCF10A cells that express doxycycline (DOX)-inducible mTwist1. Furthermore, our results showed that doxycycline-induced mTwist1 expression triggered EMT at a similar rate to TGFβ1-induced EMT in MCF10A cells. Additionally, this process was reversible upon DOX withdrawal. Thus, we have established a robust inducible EMT model in MCF10A cells, which can be used to further study cancer metastasis-driving genes.

Salt‑induced kinase 1 (SIK1) is a serine/threonine protein kinase that is a member of the AMP‑activated protein kinase family. SIK is catalytically activated through its phosphorylation by the upstream kinase LKB1. SIK1 has been reported to be associated with numerous types of cancer. The present review summarizes the structure, regulatory factors and inhibitors of SIK1, and also describes how SIK1 is a signal regulatory factor that fulfills connecting roles in various signal regulatory pathways. Furthermore, the anti‑inflammatory effects of SIK1 during the early stage of tumor occurrence and its different regulatory effects following tumor occurrence, are summarized, and through collating the tumor signal regulatory mechanisms in which SIK1 participates, it has been demonstrated that SIK1 acts as a necessary node in cancer signal transduction. In conclusion, SIK1 is discussed independent of the SIKs family, its research results and recent progress in oncology are summarized in detail with a focus on SIK1, and its potential as a therapeutic target is highlighted, underscoring the need for SIK1‑targeted regulatory strategies in future cancer therapy.

Lung cancer is the most fatal cancer worldwide. The etiology of lung cancer has yet to be fully characterized. Smoking and air pollution are several risk factors for lung cancer. Berberine, an isoquinoline alkaloid, is an antihyperglycemic, antidepressant, antioxidative, anti-inflammatory, and anticancer compound. Evidence substantiates that berberine has antitumor effects, exerting its effects by targeting a variety of cellular and molecular processes, such as apoptosis, autophagy, cell cycle arrest, migration, and metastasis. Although the beneficial effects of berberine have been reported, some limitations including low bioavailability and absorption as well as poor aqueous solubility have hindered its clinical application. Nanotechnology and nanodelivery bioformulation approaches may bypass these limitations. In addition, the combination of berberine with other therapies has been shown to result in greater treatment efficacy for lung cancer. Herein, we summarize cellular and molecular pathways that are affected by berberine, its clinical efficacy upon various combinations, and the potential for nanotechnology in lung cancer therapy.

TRAF interacting protein with forkhead associated domain (TIFA) influence progression of many cancers. However, its role in glioma remains to be explored. This study investigated the function of TIFA in glioma.

The TIFA expression in glioma and patient outcomes were analyzed using online database. Gene set enrichment analysis (GSEA) revealed related mechanisms of TIFA in glioma. TIFA's effects on glioma glycolysis and growth were assessed using in vitro and in vivo experiments. Moreover, luciferase reporter and ChIP were employed to explore the interactions among E2F1, GLUT1, HK2, and LDHA. The subcutaneous xenograft assay further elaborated the effects of TIFA in glioma.

We found overexpressed TIFA in glioma. Moreover, the high TIFA expression was associated with poor prognosis of glioma. Furthermore, GSEA indicated that overexpressed TIFA promoted E2F1 and glycolysis. Knockdown of TIFA decreased glioma development in cell and mice. TIFA knockdown down-regulated the expression of E2F1, GLUT1, HK2, and LDHA.

The study provides evidence that TIFA regulates E2F1 expression in glioma cells and promotes the proliferation, migration, and glycolysis. TIFA might be an advantageous therapeutic strategy against glioma.

DNA Fragmentation Factor (DFF) is a heterodimer protein involved in DNA fragmentation during apoptosis, which acts as a trigger downstream of caspase-3 activation. DFF40 catalytically active homo-oligomers break down chromosomal DNA. Previous scientific investigations have revealed a link between DFF40 expression changes and various cancers. DFF40 deletion or down-regulation has been observed in some cancers. Consequently, therapeutic strategies involving the DFF40 molecule compensating led to an increased rate of cancer cell apoptosis. In this review article, we aimed to introduce cancers with low expression of this protein first. The second part of this paper focuses on studies that utilized exogenous DFF40 protein produced by recombinant DNA technology and surveyed during in vitro and in vivo tests. Finally, compensation for diminished expression of the mentioned protein via gene therapy-based techniques to make up for this apoptotic molecule's low expression is the topic of the last part of this review article.

Cervical cancer (CC) is an important public health problem for women, gene expression patterns which were governed by epigenetic modifications can result in CC, CC-chemokine receptor 4 (CCR4) interacts with C-C-motif ligand 22 (CCL22) is associated with tumor progression or metastasis. A previous study by the present authors revealed the levels of chemokine CCL22 and its receptor CCR4 are increased in CC tissues, nevertheless, the regulatory mechanisms governing its expression remain poorly understood. The present study aimed to investigate the potential role of enhancer of zeste homolog 2 (EZH2)-induced epigenetic activation of CCL22/CCR4 and caused epithelial-to-mesenchymal transition (EMT) remodeling in CC. CCL22 and CCR4 were significantly up-regulated in CC samples compared with normal cervix tissues, and obvious induction of promoter DNA methylation levels of CCL22 and CCR4 was found in CC tissues. Demethylation reactivated the transcription of CCL22 and CCR4. DNA methyltransferase 3A (DNMT3A) was found to directly bind to the CCL22 and CCR4 promoter regions in vitro. Downregulation of the expression of EZH2 in CC cell lines altered DNMT3A expression and induced CCL22 and CCR4 promoters' methylation levels, while CCL22 and CCR4 mRNA expression decreased. An in vivo assay showed that EZH2 regulated the expression of CCL22/CCR4 components through DNMT3A, consistent with the in vitro results. In EZH2-silenced CC cells, migration was reduced, levels of EMT-related markers, including vimentin, slug, snail and β-catenin, were all reduced and zona occludens 1 (ZO-1) increased. In DNMT3A-silenced CC cells, migration was induced, vimentin, slug, snail and β-catenin were all induced and ZO-1 was reduced. Inhibition of CCL22 protein significantly decreased migration of CC cells and vimentin, slug, snail and β-catenin levels, while ZO-1 increased. In conclusion, EZH2 appears to regulate CCL22/CCR4 expression via epigenetic activation, causing EMT process remodeling in CC progression.

Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote the differentiation of muscle cells. However, the exact molecular mechanism underlying these functions remains unclear. Previous studies revealed that the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits muscle atrophy. Therefore, we hypothesized that the protective effect of metformin might be related to ZEB1. We investigated the positive effect of metformin on IL-1β-induced skeletal muscle atrophy by regulating ZEB1 in vitro and in vivo. Compared with the normal cell differentiation group, the metformin-treated group presented increased myotube diameters and reduced expression levels of atrophy-marker proteins. Moreover, muscle cell differentiation was hindered, when we artificially interfered with ZEB1 expression in mouse skeletal myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response to inflammatory stimulation, metformin treatment increased the expression levels of ZEB1 and three differentiation proteins, MHC, MyoD, and myogenin, whereas si-ZEB1 partially counteracted these effects. Moreover, marked atrophy was induced in a mouse model via the administration of lipopolysaccharide (LPS) to the skeletal muscles of the lower limbs. Over a 4-week period of intragastric administration, metformin treatment ameliorated muscle atrophy and increased the expression levels of ZEB1. Metformin treatment partially alleviated muscle atrophy and stimulated differentiation. Overall, our findings may provide a better understanding of the mechanism underlying the effects of metformin treatment on skeletal muscle atrophy and suggest the potential of metformin as a therapeutic drug.

The cornea, consisting of three cellular and two non-cellular layers, is the outermost part of the eyeball and frequently injured by external physical, chemical, and microbial insults. The epithelial-to-mesenchymal transition (EMT) plays a crucial role in the repair of corneal injuries. Zinc finger E-box binding homeobox 1 (ZEB1), an important transcription factor involved in EMT, is expressed in the corneal tissues. It regulates cell activities like migration, transformation, and proliferation, and thereby affects tissue inflammation, fibrosis, tumor metastasis, and necrosis by mediating various major signaling pathways, including transforming growth factor (TGF)-β. Dysfunction of ZEB1 would impair corneal tissue repair leading to epithelial healing delay, interstitial fibrosis, neovascularization, and squamous cell metaplasia. Understanding the mechanism underlying ZEB1 regulation of corneal injury repair will help us to formulate a therapeutic approach to enhance corneal injury repair.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

ZEB1 is an essential factor in embryonic development. In adults, it is often highly expressed in malignant tumors with low expression in normal tissues. The major biological function of ZEB1 in developing embryos and progressing cancers is to transdifferentiate cells from an epithelial to mesenchymal phenotype; but what roles ZEB1 plays in normal adult tissues are largely unknown. We previously reported that the reduction of Zeb1 in monoallelic global knockout (Zeb1+/-) mice reduced corneal inflammation-associated neovascularization following alkali burn. To uncover the cellular mechanism underlying the Zeb1 regulation of corneal inflammation, we functionally deleted Zeb1 alleles in Csf1r+ myeloid cells using a conditional knockout (cKO) strategy and found that Zeb1 cKO reduced leukocytes in the cornea after alkali burn. The reduction of immune cells was due to their increased apoptotic rate and linked to a Zeb1-downregulated apoptotic pathway. We conclude that Zeb1 facilitates corneal inflammatory response by maintaining Csf1r+ cell viability.

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.

The compound 1-methyltryptophan (1-MT) has been shown to act protectively in renal ischemia-reperfusion injury. Toll-like receptor 4 signaling is also a regular process of epithelial-mesenchymal transition (EMT) that can after ischemia-reperfusion injury (IRI) result in an increase in renal fibrosis. EMT is associated with specific transcription factors: Snai1, Snai2, Zeb1, and Twist. 1-MT could regulate EMT and act as an antifibrotic agent. This study aimed to investigate the effect of 1-MT on EMT transcription factors in tubular epithelial cells that underwent 30 min. Renal tubular epithelial cells (TECs) were isolated from Lewis rats using a standard protocol with Fe2O3 magnetic separation and selective media as previously mentioned. Cells were cultivated and divided into 4 groups, namely C-TECs: control cells, IRI-TECs: IRI-induced TECs, D-IRI-TECs: IRI-induced TECs treated with 1-methyl-D-tryptophan, and L-IRI-TECs: IRI-induced TECs treated with 1-methyl-L-tryptophan. IRI was induced in all groups for 30 min by mineral oil (except for C-TECs) followed by 48-hour reperfusion. RNA and proteins were isolated from harvested cells. Using a semi-quantitative polymerase chain reaction, we assessed the relative mRNA expression of EMT transcription factors Snai1, Snai2, Zeb1, and Twist. Hereby, we showed that the treatment of ischemia-induced TECs with both 1-MT isomers lowered the expression of EMT transcription factors Snai1 and Zeb1 which were increased by ischemia and reperfusion of TECs. This could act favorably in renal IRI decreasing EMT and renal fibrosis, therefore showing the potential of 1-MT as a part of therapy in renal transplantation aimed at renal ischemia-reperfusion injury.

Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR-3-65 and WXM-1-170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR-3-65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR-3-65 and WXM-1-170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR-3-65. Our study unveils a novel mechanism by which SR-3-65 and WXM-1-170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer.

Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation, differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy and targeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.

To explore the relationships among the epithelial to mesenchymal transition (EMT)-related factors (SNAIL, TWIST, and E-Cadherin) and clinicopathological parameters and gastric mesangial tumor deposits (TDs) in advanced gastric cancer (AGC) patients and their value in gastric cancer prognosis judgment.

The data of 190 patients who underwent radical resection of ACG were analyzed retrospectively, including 75 cases of TDs (+) and 115 cases of TDs (-). The expression of EMT-related transforming factors Snail, Twist, and E-cadherin in the primary tumor, paracancerous normal tissues, and TDs was detected by immunohistochemistry.

SNAIL and TWIST were overexpressed in primary tumors and TDs, whereas E-Cadherin was down-expressed in primary tumors. SNAIL was correlated significantly with tumor differentiation, lymph node metastases, and TDs (P < 0.05); TWIST was correlated strongly with tumor location, lymph node metastases, and TDs (P < 0.05); E-Cadherin was correlated closely with tumor differentiation and lymph node metastases (P < 0.05). Kaplan-Meier curves showed that SNAIL expression was correlated with DFS (P < 0.05), and TWIST expression was correlated with OS (P < 0.05). Tumor differentiation, lymph node metastasis, and TWIST expression were prognostic-independent risk factors of AGC patients (P < 0.05).

The occurrence and development of gastric cancer and the formation of TDs may be related to EMT, analyzing the expression of EMT-related transforming proteins may be helpful to judge the prognosis of gastric cancer.

The resistance of cancer cells to chemotherapy, also known as chemo-resistance, poses a significant obstacle to cancer treatment and can ultimately result in patient mortality. Epithelial-mesenchymal transition (EMT) is one of the many factors and processes responsible for chemo-resistance. Studies have shown that targeting EMT can help overcome chemo-resistance, and nanotechnology and nanomedicine have emerged as promising approaches to achieve this goal. This article discusses the potential of nanotechnology in inhibiting EMT and proposes a viable strategy to combat chemo-resistance in various solid tumors, including breast cancer, lung cancer, pancreatic cancer, glioblastoma, ovarian cancer, gastric cancer, and hepatocellular carcinoma. While nanotechnology has shown promising results in targeting EMT, further research is necessary to explore its full potential in overcoming chemo-resistance and discovering more effective methods in the future.

Senescence refers to the irreversible state in which cells enter cell cycle arrest due to internal or external stimuli. The accumulation of senescent cells can lead to many age-related diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancers. MicroRNAs are short non-coding RNAs that bind to target mRNA to regulate gene expression after transcription and play an important regulatory role in the aging process. From nematodes to humans, a variety of miRNAs have been confirmed to alter and affect the aging process. Studying the regulatory mechanisms of miRNAs in aging can further deepen our understanding of cell and body aging and provide a new perspective for the diagnosis and treatment of aging-related diseases. In this review, we illustrate the current research status of miRNAs in aging and discuss the possible prospects for clinical applications of targeting miRNAs in senile diseases.

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.

Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry.

We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion.

Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.

Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy.

In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC.

For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.

The correlation between FOXM1 and KIF20A has not been revealed in clear cell renal cell carcinoma (ccRCC).

Public data was downloaded from The Cancer Genome Atlas (TCGA) database. R software was utilized for the execution of bioinformatic analysis. The expression levels of specific molecules (mRNA and protein) were detected using real-time quantitative PCR (qRT-PCR) and Western blot assays. The capacity of cell growth was assessed by employing CCK8 and colony formation assay. Cell invasion and migration ability were assessed using transwell assay.

In our study, we illustrated the association between FOXM1 and KIF20A. Our results indicated that both FOXM1 and KIF20A were associated with poor prognosis and clinical performance. The malignant characteristics of ccRCC cells can be significantly suppressed by inhibiting FOXM1 and KIF20A, as demonstrated by in vitro experiments. Moreover, we found that FOXM1 can upregulate KIF20A. Then, EMT signaling was identified as the underlying pathway FOXM1 and KIF20A are involved. WB results indicated that FOXM1/KIF20A axis can activate EMT signaling. Moreover, we noticed that FOXM1 and KIF20A can affect the immunotherapy response and immune microenvironment of ccRCC patients.

Our results identified the role of the FOXM1/KIF20A axis in ccRCC progression and immunotherapy, making it the underlying target for ccRCC.

Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.

Reactive oxygen species (ROS) serve important homeostatic functions but must be constantly neutralized by an adaptive antioxidant response to prevent supraphysiological levels of ROS from causing oxidative damage to cellular components. Here, we report that the cellular plasticity transcription factors ZEB1 and ZEB2 modulate in opposing directions the adaptive antioxidant response to fasting in skeletal muscle. Using transgenic mice in which Zeb1 or Zeb2 were specifically deleted in skeletal myofibers, we show that in fasted mice, the deletion of Zeb1, but not Zeb2, increased ROS production and that the adaptive antioxidant response to fasting essentially requires ZEB1 and is inhibited by ZEB2. ZEB1 expression increased in fasted muscles and protected them from atrophy; conversely, ZEB2 expression in muscles decreased during fasting and exacerbated muscle atrophy. In fasted muscles, ZEB1 reduces mitochondrial damage and increases mitochondrial respiratory activity; meanwhile, ZEB2 did the opposite. Treatment of fasting mice with Zeb1-deficient myofibers with the antioxidant triterpenoid 1[2-cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoro-ethylamide (CDDO-TFEA) completely reversed their altered phenotype to that observed in fasted control mice. These results set ZEB factors as potential therapeutic targets to modulate the adaptive antioxidant response in physiopathological conditions and diseases caused by redox imbalance.

One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.

Androgen signaling inhibitors (ASI) have been approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the limited success of ASI in clinic justifies an urgent need to identify new targets and develop novel approaches for treatment. EZH2 significantly increases in prostate cancer (PCa). Little is understood, however, regarding the roles of EZH2 in Enzalutamide-resistant (EnzR) mCRPC.

We firstly investigated the levels of EZH2 and the altered pathways in public database which was comprised with primary and metastatic PCa patient tumors. To elucidate the roles of EZH2 in mCRPC, we manipulated EZH2 in EnzR PCa cell lines to examine epithelial-mesenchymal transition (EMT). To dissect the underlying mechanisms, we measured the transcription levels of EMT-associated transcription factors (TFs).

We found that EZH2 was highly expressed in mCRPC than that of primary PCa tumors and that EnzR PCa cells gained more EMT characteristics than those of enzalutamide-sensitive counterparts. Further, loss of EZH2-induced inhibition of EMT is independent of polycomb repressive complex 2 (PRC2). Mechanistically, downregulation of EZH2 inhibits transcription of EMT-associated TFs by repressing formation of H3K4me3 to the promotor regions of the TFs.

We identified the novel roles of EZH2 in EnzR mCRPC. EnzR PCa gains more EMT properties than that of enzalutamide-sensitive PCa. Loss of EZH2-assocaited inhibition of EMT is PRC2 independent. Downregulation of EZH2 suppresses EMT by impairing formation of H3K4me3 at the promotor regions, thus repressing expression of EMT-associated TFs.

Human embryonic stem cells (hESCs) can differentiate into any cell lineage. Here, we report that ZEB1 and ZEB2 promote and inhibit mesodermal-to-myogenic specification of hESCs, respectively. Knockdown and/or overexpression experiments of ZEB1, ZEB2, or PAX7 in hESCs indicate that ZEB1 is required for hESC Nodal/Activin-mediated mesodermal specification and PAX7+ human myogenic progenitor (hMuP) generation, while ZEB2 inhibits these processes. ZEB1 downregulation induces neural markers, while ZEB2 downregulation induces mesodermal/myogenic markers. Mechanistically, ZEB1 binds to and transcriptionally activates the PAX7 promoter, while ZEB2 binds to and activates the promoter of the neural OTX2 marker. Transplanting ZEB1 or ZEB2 knocked down hMuPs into the muscles of a muscular dystrophy mouse model, showing that hMuP engraftment and generation of dystrophin-positive myofibers depend on ZEB1 and are inhibited by ZEB2. The mouse model results suggest that ZEB1 expression and/or downregulating ZEB2 in hESCs may also enhance hESC regenerative capacity for human muscular dystrophy therapy.