Hyaluronic acid-mediated epithelial-mesenchymal transition of human lens epithelial cells via CD44 and TGF-β2

ABSTRACT Purpose: The epithelial-mesenchymal transition of human lens epithelial cells plays a role in posterior capsule opacification, a fibrotic process that leads to a common type of cataract. Hyaluronic acid has been implicated in this fibrosis. Studies have investigated the role of transforming growth factor (TGF)-β2 in epithelial-mesenchymal transition. However, the role of TGF-β2 in hyaluronic acid-mediated fibrosis of lens epithelial cell remains unknown. We here examined the role of TGF-β2 in the hyaluronic acid-mediated epithelial-mesenchymal transition of lens epithelial cells. Methods: Cultured human lens epithelial cells (HLEB3) were infected with CD44-siRNA by using the Lipofectamine 3000 transfection reagent. The CCK-8 kit was used to measure cell viability, and the scratch assay was used to determine cell migration. Cell oxidative stress was analyzed in a dichloro-dihydro-fluorescein diacetate assay and by using a flow cytometer. The TGF-β2 level in HLEB3 cells was examined through immunohistochemical staining. The TGF-β2 protein level was determined through western blotting. mRNA expression levels were determined through quantitative real-time polymerase chain reaction. Results: Treatment with hyaluronic acid (1.0 μM, 24 h) increased the epithelial-mesenchymal transition of HLEB3 cells. The increase in TGF-β2 levels corresponded to an increase in CD44 levels in the culture medium. However, blocking the CD44 function significantly reduced the TGF-β2-mediated epithelial-mesenchymal transition response of HLEB3 cells. Conclusions: Our study showed that both CD44 and TGF-β2 are critical contributors to the hyaluronic acid-mediated epithelial-mesenchymal transition of lens epithelial cells, and that TGF-β2 in epithelial-mesenchymal transition is regulated by CD44. These results suggest that CD44 could be used as a target for preventing hyaluronic acid-induced posterior capsule opacification. Our findings suggest that CD44/TGF-β2 is crucial for the hyaluronic acid-induced epithelial-mesenchymal transition of lens epithelial cells.

Metabolic landscape of human alveolar type II epithelial cells undergoing epithelial-mesenchymal transition induced directly by silica exposure.

Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.

Is it really descemetocele? Morphology of extremely thin membrane that remained after severe corneal melting: a case report.

The aim of this study was to report transmission electron microscopic findings of a case with whole corneal descemetocele following infective corneal ulcer for the first time in literature. A 72-year-old male patient presented with infective corneal ulcer. After resolution of the infection, corneoscleral transplantation was performed. The excised very thin corneal membrane was processed for transmission electron microscopic examination. Transmission electron microscopic examination of the specimen revealed many layered structures that consisted of two different types of cells. The first type consisted of lighter staining polygonal cells, while the second consisted of elongated cells with relatively dense staining. All cells were connected with a large number of gap or adherens junctions with intercalation of the cell membranes of adjacent cells. A haphazard distribution of cytoplasmic microfilaments were also observed in all of the cell types. There was no evidence of the presence of endothelial cells throughout the specimen. There was also no evidence of Descemet membrane presence except for a small part adjacent to iris tissue that contained some melanosomes. Although we clinically diagnosed descemetocele, Descemet membrane was not present at the electron microscopic level, and thus, the expression "descemetocele" is inappropriate.

ZNF217 Mediates Transcriptional Activation of GRHL3 to Regulate SLC22A31 and Promote Malignant Progression in Thyroid Cancer.

The incidence of thyroid cancer (THCA) has increased worldwide during the past 40 years. However, an understanding of the mechanisms and major transcription factors involved in THCA is insufficient to identify therapeutic targets against THCA. To reveal such mechanisms, we conducted bioinformatics analyses to assess the differential expression in human THCA sample and normal tissue sample, leading us to focus on the function of the ZNF217/GRHL3/ SLC22A31 axis in mediating biological activity in THCA. The genes of interest were interfered with lentiviral vectors, and transfection efficiency was verified using RT-qPCR. ZNF217, GRHL3, and SLC22A31 were abundantly expressed in THCA tissues or cells. Knockdown of GRHL3, ZNF217, or SLC22A31 all significantly curtailed the malignant biological behavior of THCA cells. ZNF217 promoted GRHL3 expression through transcriptional activation, thereby increasing the transcription of SLC22A31. Ectopic expression of GRHL3 or SLC22A31 abated the suppressing impact of ZNF217 or GRHL3 knockdown on the biological activity of THCA cells. Collectively, our results demonstrated that ZNF217 acted as an activator of GRHL3, thereby promoting the expression of SLC22A31 and the malignant activity of THCA cells.

Matrix metalloproteinases in kidney homeostasis and diseases: an update.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.

Isoliensinine suppressed gastric cancer cell proliferation and migration by targeting TGFBR1 to regulate TGF-ß-smad signaling pathways.

Background: Gastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from Nelumbo nucifera Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism. Methods: ISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, in vitro tests were used to establish the impact of ISO on GC cells. Results: Through bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-ß-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-ß-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-ß-triggered migration, invasion, and activation of the TGF-ß-Smad pathway. Conclusion: Our research suggests that ISO specifically targets TGFBR1 and regulates the TGF-ß-Smad signaling pathway to suppress the proliferation and migration of GC cells.

High glucose-induced senescence contributes to tubular epithelial cell damage in diabetic nephropathy.

Dysfunctional renal tubular epithelial cells, induced by high glucose, are commonly observed in the kidney tissues of diabetic nephropathy (DN) patients. The epithelial-mesenchymal transition (EMT) of these cells often leads to renal interstitial fibrosis and kidney damage in DN. High glucose also triggers mitochondrial damage and apoptosis, contributing further to the dysfunction of renal tubular epithelial cells. Cellular senescence, a recognized characteristic of DN, is primarily caused by high glucose. However, it remains unclear whether high glucose-induced cellular senescence in DN exacerbates the functional impairment of tubular epithelial cells. In this study, we examined the relationship between EMT and cellular senescence in kidney tissues from streptozotocin (STZ)-induced DN and HK-2 cells treated with high glucose (HG). We also investigated the impact of HG concentrations on tubular epithelial cells, specifically mitochondrial dysfunction, cellular senescence and apoptosis. These damages were primarily associated with the secretion of cytokines (such as IL-6, and TNF-α), production of reactive oxygen species (ROS), and an increase of intracellular Ca2+. Notably, resveratrol, an anti-aging agent, could effectively attenuate the occurrence of EMT, mitochondrial dysfunction, and apoptosis induced by HG. Mechanistically, anti-aging treatment leads to a reduction in cytokine secretion, ROS production, and intracellular Ca2+ levels.

Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway.

Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells. TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling. TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

Integrating Metabolic RNA Labeling-Based Time-Resolved Single-Cell RNA Sequencing with Spatial Transcriptomics for Spatiotemporal Transcriptomic Analysis.

Metabolic RNA labeling-based time-resolved single-cell RNA sequencing (scRNA-seq) has provided unprecedented tools to dissect the temporal dynamics and the complex gene regulatory networks of gene expression. However, this technology fails to reveal the spatial organization of cells in tissues, which also regulates the gene expression by intercellular communication. Herein, it is demonstrated that integrating time-resolved scRNA-seq with spatial transcriptomics is a new paradigm for spatiotemporal analysis. Metabolic RNA labeling-based time-resolved Well-TEMP-seq is first applied to profile the transcriptional dynamics of glioblastoma (GBM) cells and discover two potential pathways of EZH2-mediated mesenchymal transition in GBM. With spatial transcriptomics, it is further revealed that the crosstalk between CCL2+ malignant cells and IL10+ tumor-associated macrophages in the tumor microenvironment through an EZH2-FOSL2-CCL2 axis contributes to the mesenchymal transition in GBM. These discoveries show the power of integrative spatiotemporal scRNA-seq to elucidate the complex gene regulatory mechanism and advance the understanding of cellular processes in disease.

Cisplatin­resistant germ cell tumor models: An exploration of the epithelial­mesenchymal transition regulator SLUG.

Germ cell tumors (GCTs) constitute diverse neoplasms arising in the gonads or extragonadal locations. Testicular GCTs (TGCTs) are the predominant solid tumors in adolescents and young men. Despite cisplatin serving as the primary therapeutic intervention for TGCTs, 10­20% of patients with advanced disease demonstrate resistance to cisplatin­based chemotherapy, and epithelial­mesenchymal transition (EMT) is a potential contributor to this resistance. EMT is regulated by various factors, including the snail family transcriptional repressor 2 (SLUG) transcriptional factor, and, to the best of our knowledge, remains unexplored within TGCTs. Therefore, the present study investigated the EMT transcription factor SLUG in TGCTs. In silico analyses were performed to investigate the expression of EMT markers in TGCTs. In addition, a cisplatin­resistant model for TGCTs was developed using the NTERA­2 cell line, and a mouse model was also established. Subsequently, EMT was assessed both in vitro and in vivo within the cisplatin­resistant models using quantitative PCR and western blot analyses. The results of the in silico analysis showed that the different histologies exhibited distinct expression profiles for EMT markers. Seminomas exhibited a lower expression of EMT markers, whereas embryonal carcinomas and mixed GCT demonstrated high expression. Notably, patients with lower SLUG expression had longer median progression­free survival (46.4 months vs. 28.0 months, P=0.022). In the in vitro analysis, EMT­associated genes [fibronectin; vimentin (VIM); actin, α2, smooth muscle; collagen type I α1; transforming growth factor­ß1; and SLUG] were upregulated in the cisplatin­resistant NTERA­2 (NTERA­2R) cell line after 72 h of cisplatin treatment. Consistent with this finding, the NTERA­2R mouse model demonstrated a significant upregulation in the expression levels of VIM and SLUG. In conclusion, the present findings suggested that SLUG may serve a crucial role in connecting EMT with the development of cisplatin resistance, and targeting SLUG may be a putative therapeutic strategy to mitigate cisplatin resistance.

SOX17 Prevents Endothelial-Mesenchymal Transition of Pulmonary Arterial Endothelial Cells in Pulmonary Hypertension through Mediating TGF-ß/Smad2/3 Signaling.

Endothelial to mesenchymal transition (EndMT) has been reported to cause pulmonary vascular remodeling of pulmonary hypertension (PH). We have demonstrated that SOX17, a member of the SRY-Box (SOX) transcription factor family, affects pulmonary artery vascular homeostasis through exosomes in an autocrine and paracrine manner. However, the role of SOX17 in mediating EndMT of pulmonary arterial endothelial cells (PAECs) in PH and its underlying intracellular mechanisms are not yet clarified. Here, we show that in the remodeling pulmonary vascular of idiopathic PH patients and Sugen 5416/hypoxia (Sugen/hypoxia)-induced PH rats, the downregulation of SOX17 expression was accompanied by a significant pulmonary arterial EndMT and TGF-ß/Smad2/3 signaling activation. In primary HPAECs, the expression of SOX17 was inhibited by canonical TGF-ß signaling. SOX17 overexpression reversed TGF-ß- and hypoxia-induced EndMT. It is suggested that SOX17 is required for HPAECs to acquire TGF-ß-mediated EndMT. Mechanistically, SOX17 prevented TGF-ß-induced EndMT of PAECs through trans-suppressing ROCK1 expression by binding to the specific promoter region of ROCK1, thereby inhibiting the phosphorylation of MYPT1 and MLC. Further, we found that Tie2-Cre rats with endothelial cell-specific SOX17 overexpression were prevented from Sugen/hypoxia-induced EndMT and pulmonary vascular remodeling. In keeping with the in vitro data, compared with the Tie2-Cre rats treated by Sugen/hypoxia, the rats with SOX17 overexpression showed decreased expression of ROCK1 as well as the MYPT1 and MLC phosphorylation. Overall, our studies demonstrate a novel TGF-ß/SOX17/ROCK1 pathway regulating EndMT of PAECs and propose SOX17 as a potential target for exploring therapeutics to alleviate pulmonary vascular remodeling in PH.

Disruption of blood-brain barrier and endothelial-to-mesenchymal transition are attenuated by Astragalus polysaccharides mediated through upregulation of ETS1 expression in experimental autoimmune encephalomyelitis.

Blood-brain barrier (BBB) breakdown, an early hallmark of multiple sclerosis (MS), remains crucial for MS progression. Our previous works have confirmed that Astragalus polysaccharides (APS) can significantly ameliorate demyelination and disease progression in experimental autoimmune encephalomyelitis (EAE) mice. However, it remains unclear whether APS protects BBB and the potential mechanism. In this study, we found that APS effectively reduced BBB leakage in EAE mice, which was accompanied by a decreased level of endothelial-to-mesenchymal transition (EndoMT) in the central nervous system (CNS). We further induced EndoMT in the mouse brain endothelial cells (bEnd.3) by interleukin-1ß (IL-1ß) in vitro. The results showed that APS treatment could inhibit IL-1ß-induced EndoMT and endothelial cell dysfunction. In addition, the transcription factor ETS1 is a central regulator of EndoMT related to the compromise of BBB. We tested the regulation of APS on ETS1 and identified the expression of ETS1 was upregulated in both EAE mice and bEnd.3 cells by APS. ETS1 knockdown facilitated EndoMT and endothelial cell dysfunction, which completely abolished the regulatory effect of APS. Collectively, APS treatment could protect BBB integrity by inhibiting EndoMT, which might be associated with upregulating ETS1 expression. Our findings indicated that APS has potential value in the prevention of MS.

Mesoporous cerium oxide nanoenzyme for Efficacious impeding tumor and metastasis via Conferring resistance to anoikis.

Tumor cells can survive when detached from the extracellular matrix or lose cell-to-cell connections, leading to a phenomenon known as anoikis resistance (AR). AR is closely associated with the metastasis and proliferation of tumor cells, enabling them to disseminate, migrate, and invade after detachment. Here, we have investigated a novel composite nanoenzyme comprising mesoporous silica/nano-cerium oxide (MSN-Ce@SP/PEG). This nanoenzyme exhibited satisfactory catalase (CAT) activity, efficiently converting high levels of H2O2 within tumor cells into O2, effectively alleviating tumor hypoxia. Furthermore, MSN-Ce@SP/PEG nanoenzyme demonstrated high peroxidase (POD) activity, elevating reactive oxygen species (ROS) levels and attenuating AR in hepatocellular carcinoma (HCC) cells. The MSN-Ce@SP/PEG nanoenzyme exhibited satisfactory dual bioactivity in CAT and POD and was significantly enhanced under favorable photothermal conditions. Through the synergistic effects of these capabilities, the nanoenzyme disrupted the epithelial-mesenchymal transition (EMT) process in detached HCC cells, ultimately inhibiting the recurrence and metastasis potential of anoikis-resistant HCC cells. This study represents the first report of a novel nanoenzyme based on mesoporous silica/nano-cerium oxide for treating AR in HCC cells, thereby suppressing HCC recurrence and metastasis. The findings of this work offer a pioneering perspective for the development of innovative strategies to prevent the recurrence and metastasis of HCC.

Actinidia chinensis polysaccharide interferes with the epithelial-mesenchymal transition of gastric cancer by regulating the nuclear transcription factor-κB pathway to inhibit invasion and metastasis.

OBJECTIVE: To investigate the mechanisms of the effect of Actinidia chinensis polysaccharide (ACPS) on the invasion and metastasis of gastric cancer cells. METHODS: BGC-823-Luc gastric cancer cells stably transfected with a luciferase gene were used to establish an insitutransplanted tumor mouse model. A live mouse imaging system was used to observe tumor growth, and hematoxylin and eosin staining was applied to analyze tissue histopathology. Transwell and scratch wound assays were performed to examine the invasive and migratory ability of BGC-823 cells. Immunofluorescence, confocal microscopy, immunohistochemistry, and Western blot assays were used to analyze the expressions of the nuclear transcription factor-κB (NF-κB) signaling pathway and epithelial-mesenchymal transition (EMT)-related proteins. RESULTS: ACPS significantly inhibited the growth of subcutaneously transplanted BGC-823-Luc gastric cancer tumors in nude mice and reduced inflammatory cell infiltration in tumor tissues. ACPS inhibited Epidermal Growth Factor-induced invasion, migration, and morphological changes in the cytoskeleton of BGC-823 cells. ACPS inhibited gastric cancer EMT and decreased the expression of matrix metallopeptidase 9, N-cadherin and p-NF-κB p65 in transplanted tumor tissues. ACPS inhibited the expression of matrix metalloproteinases and vascular adhesion factors in BGC-823 cells, promoted p65-NF-κB nuclear translocation, and regulated proteins associated with the NF-κB p65 pathway. CONCLUSIONS: ACPS inhibited gastric cancer invasion and metastasis both in vivo and in vitro, which evidenced the inhibition of gastric cancer EMT viaregulating the NF-κB inflammatory pathway.

Activating Invasion and Metastasis in Small Cell Lung Cancer: Role of the Tumour Immune Microenvironment and Mechanisms of Vasculogenesis, Epithelial-Mesenchymal Transition, Cell Migration, and Organ Tropism.

BACKGROUND: Small cell lung cancer (SCLC) harbours the most aggressive phenotype of all lung cancers to correlate with its bleak prognosis. The aggression of SCLC is partially attributable to its strong metastatic tendencies. The biological processes facilitating the metastasis in SCLC are still poorly understood and garnering a deeper understanding of these processes may enable the exploration of additional targets against this cancer hallmark in the treatment of SCLC. RECENT FINDINGS: This narrative review will discuss the proposed molecular mechanisms by which the cancer hallmark of activating invasion and metastasis is featured in SCLC through important steps of the metastatic pathway, and address the various molecular targets that may be considered for therapeutic intervention. The tumour immune microenvironment plays an important role in facilitating immunotherapy resistance, whilst the poor infiltration of natural killer cells in particular fosters a pro-metastatic environment in SCLC. SCLC vasculogenesis is achieved through VEGF expression and vascular mimicry, and epithelial-mesenchymal transition is facilitated by the expression of the transcriptional repressors of E-cadherin, the suppression of the Notch signalling pathway and tumour heterogeneity. Nuclear factor I/B, selectin and B1 integrin hold important roles in SCLC migration, whilst various molecular markers are expressed by SCLC to assist organ-specific homing during metastasis. The review will also discuss a recent article observing miR-1 mRNA upregulation as a potential therapeutic option in targeting the metastatic activity of SCLC. CONCLUSION: Treatment of SCLC remains a clinical challenge due to its recalcitrant and aggressive nature. Amongst the many hallmarks used by SCLC to enable its aggressive behaviour, that of its ability to invade surrounding tissue and metastasise is particularly notable and understanding the molecular mechanisms in SCLC metastasis can identify therapeutic targets to attenuate SCLC aggression and improve mortality.

USP5 promotes tumor progression by stabilizing SLUG in bladder cancer.

Bladder cancer ranks as the second most prevalent urology malignancy globally. Invasive metastasis is a significant contributor to mortality among patients with bladder cancer, yet the underlying mechanisms remain elusive. Deubiquitinases are pivotal in carcinogenesis, with USP5 implicated in the malignant progression of hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer. The present study assessed the role and mechanism of ubiquitin-specific proteinase 5 (USP5) in the malignant progression of bladder cancer. The association between USP5 expression and bladder cancer prognosis and stage was analyzed using The Cancer Genome Atlas database. Moreover, to elucidate the role of USP5 in bladder cancer, USP5 overexpression and knockdown cell lines were established using T24 cells. Cell viability, proliferation and migration were assessed using Cell Counting Kit-8, Transwell and scratch assays, respectively. Cyclohexanamide was used to evaluate the effect of USP5 expression on Snail family zinc finger 2 (SLUG) stability. Immunoprecipitation and immunofluorescence co-localization were utilized to probe the interaction between USP5 and SLUG. Changes in mRNA and protein levels were assessed using reverse transcription-quantitative PCR and western blotting, respectively. The results revealed that patients with bladder cancer with high USP5 expression had significantly shorter survival (P<0.05) and a higher clinicopathologic stage (P<0.05) than those with low USP5 expression. T24 cells overexpressing USP5 demonstrated significantly increased proliferation (P<0.05), invasion (P<0.05) and expression of epithelial-mesenchymal transition markers (P<0.05); whereas T24 cells with knocked-down USP5 expression revealed significantly reduced proliferation (P<0.05), invasion (P<0.05) and epithelial-mesenchymal transition markers (P<0.05). Immunoprecipitation experiments demonstrated the binding of USP5 to SLUG in bladder cancer cells, with further analysis revealing that USP5 upregulated protein levels of SLUG by inhibiting its ubiquitination. Furthermore, the treatment of bladder cancer cells with Degrasyn, a USP5 inhibitor, was associated with a significant inhibition of the proliferation (P<0.05) and invasion (P<0.05) of T24 cells. In conclusion, the findings of the present study underscore the role of USP5 in promoting the malignant progression of bladder cancer through the stabilization of SLUG. Targeting USP5 holds promise as a strategy for inhibiting bladder cancer progression.

A Comparative immunohistochemical analysis of epithelial-mesenchymal transition biomarkers in odontogenic keratocyst, dentigerous cyst, and radicular cyst.

Background: Odontogenic keratocyst (OKC) is one of the common odontogenic cysts with aggressive clinical behavior and a high recurrence rate. Epithelial-mesenchymal transition (EMT) is a process, in which the epithelial cell loses its epithelial characteristics and acquires mesenchymal features. Since the evidence for the involvement of EMT in the development of OKC is still limited, the present study aimed to investigate the immunohistochemical expression of EMT-related proteins (E-cadherin and N-cadherin) in OKC and compare them to radicular cyst (RC) and dentigerous cyst (DC). Materials and Methods: In this descriptive analytical study, 75 paraffin blocks, including 25 DCs, 25 OKC, and 25 RCs, were selected. Immunohistochemical staining was performed to determine the expression and staining intensity of E-cadherin and N-cadherin proteins. The specimens were examined under an optical microscope, and the data were analyzed using the Kruskal-Wallis test in SPSS statistical software (version 23) with a significance level of 5%. Results: The expression of N-cadherin in OKC was higher than that in other cysts; nonetheless, there was no statistically significant difference (P = 0.331). The staining intensity of N-cadherin was weak in most cases, and this difference was not statistically significant (P = 0.252). E-cadherin expression in OKC was significantly lower than that in radicular and DCs (P = 0.003). In addition, the staining intensity of E-cadherin in OKC was weak and moderate (P = 0.003). Conclusion: In this study, we observed an increase in the expression of N-cadherin in OKC. In addition, the protein expression levels of E-cadherin in OKC were significantly lower compared to DC and RC. Therefore, it appears that the EMT process likely occurs in OKC and may contribute to its local aggressive behavior.

Association between the Worst Pattern of Tumor Invasion and Epithelial-mesenchymal Transition and their Prognostic Impact on Early-stage Oral Tongue Squamous Cell Carcinoma.

Purpose: We aimed to determine the association between the worst pattern of tumor invasion (WPOI) and epithelial-mesenchymal transition (EMT) in early-stage oral tongue squamous cell carcinoma (OTSCC) with no adverse features and their impact on 2-year disease-free survival (DFS) and overall survival (OS) rates. Methods: This prospective observational study included treatment-naive 50 patients who underwent primary surgery for OTSCC (pT1T2N0M0; AJCC 8th edition, with no adverse features) from June 1, 2020, to March 31, 2021 (minimum follow-up period, 2 years). WPOI (low- or high-invasive) and EMT (E-cadherin, N-cadherin, and vimentin expression at the tumor invasive front) were assessed. Results: High invasive WPOI was seen in 66% and low invasive in 34%. 80% of the patients had EMT. No statistically significant association was found between WPOI and EMT. The OS and DFS at 2 years were 90% and 80% respectively. WPOI had statistically significant impact on 2-year DFS (100% for low & 69.7% for high, p-value 0.014). EMT did not significantly affect DFS or OS rates. Conclusions: In early stage OTSCC with no adverse features, WPOI can be a promising predictor for disease recurrence. However, this should be validated for modifying treatment guidelines.

Drosophila anterior midgut internalization via collective epithelial-mesenchymal transition at the embryo surface and enclosure by surrounding tissues.

Internal organ development requires cell internalization, which can occur individually or collectively. The best characterized mode of collective internalization is epithelial invagination. Alternate modes involving collective mesenchymal behaviours at the embryo surface have been documented, but their prevalence is unclear. The Drosophila embryo has been a major model for the study of epithelial invaginations. However, internalization of the Drosophila anterior midgut primordium is incompletely understood. Here, we report that an epithelial-mesenchymal transition (EMT) occurs across the internalizing primordium when it is still at the embryo surface. At the earliest internalization stage, the primordium displays less junctional DE-cadherin than surrounding tissues but still exhibits coordinated epithelial structure as it invaginates with the ventral furrow. This initial invagination is transient, and its loss correlates with the activation of an associated mitotic domain. Activation of a subsequent mitotic domain across the broader primordium results in cell divisions with mixed orientations that deposit some cells within the embryo. However, cell division is non-essential for primordium internalization. Post-mitotically, the surface primordium displays hallmarks of EMT: loss of adherens junctions, loss of epithelial cell polarity, and gain of cell protrusions. Primordium cells extend over each other as they internalize asynchronously as individuals or small groups, and the primordium becomes enclosed by the reorganizations of surrounding epithelial tissues. We propose that collective EMT at the embryo surface promotes anterior midgut internalization through both inwardly-directed divisions and movements of its cells, and that the latter process is facilitated by surrounding tissue remodeling.

Adaptor protein Abelson interactor 1 in homeostasis and disease.

Dysregulation of Abelson interactor 1 (ABI1) is associated with various states of disease including developmental defects, pathogen infections, and cancer. ABI1 is an adaptor protein predominantly known to regulate actin cytoskeleton organization processes such as those involved in cell adhesion, migration, and shape determination. Linked to cytoskeleton via vasodilator-stimulated phosphoprotein (VASP), Wiskott-Aldrich syndrome protein family (WAVE), and neural-Wiskott-Aldrich syndrome protein (N-WASP)-associated protein complexes, ABI1 coordinates regulation of various cytoplasmic protein signaling complexes dysregulated in disease states. The roles of ABI1 beyond actin cytoskeleton regulation are much less understood. This comprehensive, protein-centric review describes molecular roles of ABI1 as an adaptor molecule in the context of its dysregulation and associated disease outcomes to better understand disease state-specific protein signaling and affected interconnected biological processes.