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.

FERMT1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by activating EGFR/AKT/ß-catenin and EGFR/ERK pathways.

OBJECTIVE: This study aimed to investigate the effects of fermitin family member 1 (FERMT1) on epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) via the EGFR/AKT/ß-catenin and EGFR/ERK pathways. METHODS: The expression of FERMT1 encoding protein kindlin-1 in HCC tissues was determined by immunohistochemistry, and FERMT1 mRNA expression in HCC tissues and cell lines was analyzed by qRT-PCR. After the FERMT1 expression of SNU182 and SNU387 interfered with siRNA, the cell viability, invasion, migration, and EMT were tested by CCK-8, transwell invasion, scratching, immunofluorescence/WB, respectively. Similarly, the effects of FERMT1 on the viability and metastasis of HCC were investigated in transplanted tumor and lung metastasis mouse models. The protein expressions of EGFR/AKT/ß-catenin and EGFR/ERK pathways were analyzed by WB. In addition, the relationship between FERMT1 and EGFR was further determined by immunofluorescence double staining and Co-IP. RESULTS: FERMT1 was significantly upregulated in HCC, and silencing FERMT1 inhibited the viability, invasion, migration, and EMT of HCC. Silencing FERMT1 also inhibited the activation of EGFR/AKT/ß-catenin and EGFR/ERK pathways. In addition, inhibition of EGFR, AKT, or ERK confirmed that EGFR/AKT/ß-catenin and EGFR/ERK pathways were involved in the promoting effects of FERMT1 on HCC. Co-IP and immunofluorescence experiments confirmed the targeting relationship between FERMT1 and EGFR. CONCLUSION: FERMT1 was highly expressed in HCC and promoted viability, invasion, migration, and EMT of HCC by targeting EGFR to activate the EGFR/AKT/ß-catenin and EGFR/ERK pathways. Our study revealed the role of FERMT1 in HCC and suggested that FERMT1 exerts biological effects through activating the EGFR/AKT/ß-catenin and EGFR/ERK pathways.

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.

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.

Cytoglobin attenuates melanoma malignancy but protects melanoma cells from ferroptosis.

Cutaneous malignant melanoma is the most aggressive and the deadliest form of skin cancer. There are two types of limitations which universally exist in current melanoma therapy: Adverse effects and reduced efficiency. Cytoglobin (CYGB), an iron hexacoordinated globin, is highly enriched in melanocytes and frequently epigenetically silenced during melanoma genesis. The present study aimed to explore its potential role as a biomarker for ferroptosis treatment. It was observed that B16F10 and A375 melanoma cells with loss of CYGB expression were highly sensitive to ferroptosis inducers RSL3 and erastin, whereas G361 melanoma cells with highly enriched CYGB were resistant to RSL3 or erastin. Ectopically overexpressed CYGB rendered B16F10 and A375 cells resistant to RSL3 or erastin, accompanied by decreased proliferation and epithelial­mesenchymal transition (EMT). By contrast, knockdown of CYGB expression made G361 cells sensitive to ferroptosis induction but induced proliferation and EMT progression of G361 cells. Mechanistically, CYGB­induced resistance of melanoma cells to ferroptosis may have been associated, in part, with i) Suppression of EMT; ii) upregulation of glutathione peroxidase 4 expression; iii) decrease of labile iron pool. In vivo study also demonstrated that CYGB overexpression rendered xenograft melanoma much more resist to RSL3 treatment. Based on these findings, CYGB is a potential therapeutic biomarker to screen the melanoma patients who are most likely benefit from ferroptosis treatment.

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.

Lens capsule advanced glycation end products induce senescence in epithelial cells: Implications for secondary cataracts.

Posterior capsule opacification (PCO) is a common complication after cataract surgery. Residual lens epithelial cells (LECs) on the anterior lens capsule, after cataract surgery, migrate to the posterior lens capsule and undergo transdifferentiation into myofibroblast-like cells. Those cells synthesize excessive amounts of extracellular matrix and contribute to fibrosis during PCO. Cellular senescence, a phenomenon that increases with aging, has been implicated in several fibrotic diseases. Here, we have investigated the prevalence of senescent LECs within the lens posterior capsule and the ability of advanced glycation end products (AGEs) in lens capsules to induce senescence, contributing to PCO. Aged lens capsules from pseudophakic human cadaver eyes showed the presence of senescent LECs. In human capsular bags, LECs showed an age-dependent increase in senescence after 28 days of culture. Human LECs cultured on aged lens capsules for 3 days underwent senescence; this effect was not seen in LECs cultured on young lens capsules. Human LECs cultured on an AGE-modified extracellular matrix (ECM-AGEs) showed an AGE-concentration-dependent increase in the expression of senescence markers and reactive oxygen species (ROS) levels. Treatment with a RAGE antagonist and ROS inhibitor reduced the expression of senescence and fibrotic markers. Additionally, conditioned media from ECM-AGEs-treated cells induced the expression of fibrotic markers in naïve LECs. Together, these suggest that AGEs in the capsule induce senescence of LECs, which triggers the mesenchymal transition of neighboring non-senescent LECs and contributes to PCO.

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.

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.

Epithelial-Mesenchymal Transition Indexes in Triple-Negative Breast Cancer Progression and Metastases.

Background Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the lack of expression of estrogen and progesterone receptors and the absence of HER2 protein overexpression or gene amplification. How TNBC becomes so aggressive at the molecular level is not yet fully understood. The epithelial-mesenchymal transition (EMT) has been increasingly recognized as playing a pivotal role in cancer progression and metastasis. This study aimed to elucidate the connection between TNBC progression with EMT-related markers, including vimentin, beta-catenin, and E-cadherin. Methodology Rigorous immunohistochemical analysis was employed to assess the expression of vimentin, beta-catenin, and E-cadherin in primary tumors, tumor buds, and lymph node metastases (LNMs) from 137 cases with an invasive ductal carcinoma triple-negative phenotype diagnosed between 2018 and 2024. The EMT index, which was especially important in our work, is the sum of vimentin and beta-catenin expression divided by that of E-cadherin. Estimated Pearson correlation, multiple linear regression, and Kruskal-Wallis tests were used to determine the relationships of the EMT index with tumor buds and tumor-infiltrating lymphocytes (TILs). Results Vimentin highly correlated within separate regions of interest with Pearson correlation ranging from 0.90 to 0.92 (p < 0.001). Strong negative correlations between E-cadherin and vimentin (r = -0.81 to - 0.89, p < 0.001) showed its role in preserving the epithelial phenotype. The presence of tumor buds, aggregates, or clusters of cancer cells shed from the primary tumor mass invading the connective tissue showed very strong associations with the EMT index (r = 0.91, p < 0.001). Its presence is suggestive of aggressive disease and may identify a high-risk subpopulation that may benefit from more active surveillance or adjuvant treatment. Similarly, TILs correlated inversely with the EMT index (r = -0.90, p < 0.001). The most significant predictor of the EMT index, i.e., vimentin, had a model R-squared value of 1.000 in the regression analysis. Conclusions This study brings to light the importance of EMT-related markers in TNBC progression, with special emphasis on tumor buds as possible prognostic indicators for aggressive disease. The negative correlation of TILs with the EMT index indicates that an effective immune response could antagonize EMT-mediated tumor progression. These results suggest that EMT-based treatments in TNBC should be designed from a multimarker perspective by including interactions among several markers to optimize predictions and therapeutics. The results hold the potential to set future research directions and actionable outcomes that could influence clinical utility in the battle against TNBC.

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.

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.

miR-6884-5p inhibits proliferation and epithelial-mesenchymal transition in non-small cell lung cancer cells.

Background: Non-small cell lung cancer (NSCLC) is associated with a high mortality and morbidity rate. MicroRNAs participate in tumorigenesis, progression and metastasis of NSCLC. However, miR-6884-5p has not been previously studied. This study aimed to investigate the role of miR-6884-5p in NSCLC and explore its underlying mechanisms. Methods: We used miR-6884-5p mimics and inhibitors to assess its effects in NSCLC. miR-6884-5p expression levels in NSCLC cell lines were quantified using qRT-PCR. Cell viability was determined using a cell-counting kit 8 assay. Western blot analysis was employed to measure apoptotic proteins. The impact of miR-6884-5p on cell proliferation was assessed via colony formation assay. Furthermore, Transwell assays were utilized to visualize and quantify the effects of miR-6884-5p on NSCLC migration and invasion. Results: miR-6884-5p mimic significantly inhibited NSCLC cell proliferation to 71.21 % and 72.26 % of control at 5 days of culture time in H460 and HC9 cells (both p < 0.01), respectively, while miR-6884-5p inhibitor significantly promoted cell proliferation to 119.66 % and 126.44 % of control at 5 days of culture time in H460 and HC9 cells (both p < 0.05), respectively. In addition, miR-6884-5p promoted apoptosis by reducing the anti-apoptotic protein B-cell lymphoma 2 (BCL2) protein and increasing apoptotic protein BCL2 associated X protein (all p < 0.01 at least). Moreover, miR-6884-5p effectively suppressed transforming growth factor ß1-induced epithelial-mesenchymal transition, as evidenced by the restored expression of E-cadherin (p < 0.01), N-cadherin (p < 0.01) and Vimentin (p < 0.05), leading to the inhibition of migration and invasion in NSCLC cell lines. Conclusions: Our findings demonstrate that miR-6884-5p can inhibit NSCLC cell proliferation, migration, and invasion, suggesting its potential as a therapeutic target for NSCLC treatment.

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.

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.

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.

GAMG ameliorates silica-induced pulmonary inflammation and fibrosis via the regulation of EMT and NLRP3/TGF-ß1/Smad signaling pathway.

Silicosis is an occupational disease caused by exposure to silica characterized by pulmonary inflammation and fibrosis, for which there is a lack of effective drugs. Glycyrrhetinic acid 3-O-ß-D-glucuronide (GAMG) can treat silicosis due to its anti-inflammatory and anti-fibrotic properties. Here, the effect of therapeutic interventions of GAMG was evaluated in early-stage and advanced silicosis mouse models. GAMG significantly improved fibrotic pathological changes and collagen deposition in the lungs, alleviated lung inflammation in the BALF, reduced the expression of TNF-α, IL-6, NLRP3, TGF-ß1, vimentin, Col-Ⅰ, N-cadherin, and inhibited epithelial-mesenchymal transition (EMT), thereby ameliorating pulmonary fibrosis. Moreover, the dose of 100 mg/kg GAMG can effectively prevent early-stage silicosis, while that of 200 mg/kg was recommended for advanced silicosis. In vitro and in vivo study verified that GAMG can suppress EMT through the NLRP3/TGF-ß1/Smad2/3 signaling pathway. Therefore, GAMG could be a promising preventive (early-stage silicosis) and therapeutic (advanced silicosis) strategy, which provides a new idea for formulating prevention and treatment strategies.