Mechanoresponsive regulation of tissue regeneration during distraction osteogenesis.

Distraction osteogenesis is widely used for bone tissue engineering. Mechanical stimulation plays a central role in the massive tissue regeneration observed during distraction osteogenesis. Although distraction osteogenesis has been a boon for patients with bone defects, we still have limited knowledge about the intrinsic mechanotransduction that converts physical forces into biochemical signals capable of inducing cell behavior changes and new tissue formation. In this review, we summarize the findings for mechanoresponsive factors, including cells, genes, and signaling pathways, during the distraction osteogenesis different phases. These elements function for coupling of osteogenesis and angiogenesis via the Integrin-FAK, TGF-ß/BMP, Wnt/ß-catenin, Hippo, MAPK, PI3K/Akt, and HIF-1α signaling pathways in a mechanoresponsive niche. The available evidence further suggests the existence of a balance between the epithelial-mesenchymal transition and mesenchymal-epithelial transition under hypoxic stress. We also briefly summarize the current in silico simulation algorithms and propose several future research directions that may advance understanding of distraction osteogenesis in the era of bioinformation, particularly the integration of artificial intelligence models with reliable single-cell RNA sequencing datasets. The objective of this review is to utilize established knowledge to further optimize existing distraction protocols and to identify potential therapeutic targets.

Hippo pathway effectors YAP, TAZ and TEAD are associated with EMT master regulators ZEB, Snail and with aggressive phenotype in phyllodes breast tumors.

BACKGROUND: Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms that tend to recur locally and may have metastatic potential. Their pathogenesis is poorly understood. Hippo signaling pathway plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. Hippo signaling dysfunction has been implicated in cancer. Recent evidence suggests that there is cross-talk between the Hippo signaling key proteins YAP/TAZ and the epithelial-mesenchymal transition (EMT) master regulators Snail and ZEB. In this study we aimed to investigate the expression of Hippo signaling pathway components and EMT regulators in PTs, in relation to tumor grade. METHODS: Expression of Hippo signaling effector proteins YAP, TAZ and their DNA binding partner TEAD was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 86 human phyllodes breast tumors (45 benign, 21 borderline, 20 malignant), in comparison with tumor grade and with the expression of EMT-related transcription factors ZEB and Snail. RESULTS: Nuclear immunopositivity for YAP, TAZ and TEAD was detected in both stromal and epithelial cells in PTs and was significantly higher in high grade tumors. Interestingly, there was a significant correlation between the expression of YAP, TAZ, TEAD and the expression of ZEB and SNAIL. CONCLUSIONS: Our results originally implicate Hippo signaling pathway in PTs pathogenesis and suggest that an interaction between Hippo signaling key components and EMT regulators may promote the malignant features of PTs.

Hyaluronic acid-mediated epithelial-mesenchymal transition of human lens epithelial cells via CD44 and TGF-ß2.

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)-ß2 in epithelial-mesenchymal transition. However, the role of TGF-ß2 in hyaluronic acid-mediated fibrosis of lens epithelial cell remains unknown. We here examined the role of TGF-ß2 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-ß2 level in HLEB3 cells was examined through immunohistochemical staining. The TGF-ß2 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-ß2 levels corresponded to an increase in CD44 levels in the culture medium. However, blocking the CD44 function significantly reduced the TGF-ß2-mediated epithelial-mesenchymal transition response of HLEB3 cells. CONCLUSIONS: Our study showed that both CD44 and TGF-ß2 are critical contributors to the hyaluronic acid-mediated epithelial-mesenchymal transition of lens epithelial cells, and that TGF-ß2 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-ß2 is crucial for the hyaluronic acid-induced epithelial-mesenchymal transition of lens epithelial cells.

Mesothelin promotes the migration of endometrioid carcinoma and is associated with the MELF pattern.

Mesothelin (MSLN) is expressed in the mesothelium in normal tissues but is overexpressed in various malignant tumors. In this study, we searched for genes that were more frequently expressed in cases of endometrioid carcinoma (EC) with the MELF (microcystic, elongated, and fragmented) pattern using laser microdissection and RNA sequencing, and found that MSLN was predominantly expressed in cases with the MELF pattern. The role of MSLN in EC was analyzed by generating MSLN-knockout and -knockdown EC cell lines. MSLN promoted migration and epithelial-mesenchymal transition (EMT). Moreover, we found that cadherin-6 (CDH6) expression was regulated by MSLN. MSLN is known to bind to cancer antigen 125 (CA125), and we found that CA125 can regulate CDH6 expression via MSLN. Immunohistochemical investigations showed that MSLN, CA125, and CDH6 expression levels were considerably elevated in EC with the MELF pattern. The expression of CA125 was similar to that of MSLN not only in terms of immunohistochemical staining intensity but also the blood level of CA125. Our results showed that MSLN contributes to the migration and EMT of EC cells through upstream CA125 and downstream CDH6. Therefore, MSLN has potential as a therapeutic target for EC with the MELF pattern.

Unveiling the pathological functions of SOCS in colorectal cancer: Current concepts and future perspectives.

Colorectal cancer (CRC) remains a significant global health challenge, marked by increasing incidence and mortality rates in recent years. The pathogenesis of CRC is complex, involving chronic inflammation of the intestinal mucosa, heightened immunoinflammatory responses, and resistance to apoptosis. The suppressor of cytokine signaling (SOCS) family, comprised of key negative regulators within cytokine signaling pathways, plays a crucial role in cell proliferation, growth, and metabolic regulation. Deficiencies in various SOCS proteins can trigger the activation of the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathways, following the binding of cytokines and growth factors to their receptors. Mounting evidence indicates that SOCS proteins are integral to the development and progression of CRC, positioning them as promising targets for novel anticancer therapies. This review delves into the structure, function, and molecular mechanisms of SOCS family members, examining their roles in cell proliferation, apoptosis, migration, epithelial-mesenchymal transition (EMT), and immune modulation. Additionally, it explores their potential impact on the regulation of CRC immunotherapy, offering new insights and perspectives that may inform the development of innovative therapeutic strategies for CRC.

Tankyrase1/2 inhibitor XAV-939 reverts EMT and suggests that PARylation partially regulates aerobic activities in human hepatocytes and HepG2 cells.

The maintenance of a highly functional metabolic epithelium in vitro is challenging. Metabolic impairments in primary human hepatocytes (PHHs) over time is primarily due to epithelial-to-mesenchymal transitioning (EMT). The immature hepatoma cell line HepG2 was used as an in vitro model to explore strategies for enhancing the hepatic phenotype. The phenotypic characterization includes measuring the urea cycle, lipid storage, tricarboxylic acid-related metabolites, reactive oxygen species, endoplasmic reticulum calcium efflux, mitochondrial membrane potentials, oxygen consumptions rate, and CYP450 biotransformation capacity. Expression studies were performed with transcriptomics, co-immunoprecipitation and proteomics. CRISPR/Cas9 was also employed to genetically engineer HepG2 cells. After confirming that PHHs develop an EMT phenotype, expression of tankyrase1/2 was found to increase over time. EMT was reverted when blocking tankyrases1/2-dependent poly-ADP-ribosylation (PARylation) activity, by biochemical and genetic perturbation. Wnt/ß-catenin inhibitor XAV-939 blocks tankyrase1/2 and treatment elevated several oxygen-consuming reactions (electron-transport chain, OXHPOS, CYP450 mono-oxidase activity, phase I/II xenobiotic biotransformation, and prandial turnover), suggesting that cell metabolism was enhanced. Glutathione-dependent redox homeostasis was also significantly improved in the XAV-939 condition. Oxygen consumption rate and proteomics experiments in tankyrase1/2 double knockout HepG2 cells then uncovered PARylation as master regulator of aerobic-dependent cell respiration. Furthermore, novel tankyrase1/2-dependent PARylation targets, including mitochondrial DLST, and OGDH, were revealed. This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures.

Sestrin2 Restricts Endothelial-to-Mesenchymal Transition Induced by Lipolysaccharide via Autophagy.

OBJECTIVES: Endothelial-to-mesenchymal transition (EndoMT) is a significant biological phenomenon wherein endothelial cells undergo a loss of their endothelial traits and progressively acquire mesenchymal characteristics. Consequently, this transformation leads to both a compromised ability to maintain lumen permeability and alterations in vascular structure, which hampers the preservation of blood-brain barrier integrity. This study aimed to investigate inflammation-induced EndoMT and its etiology, with the goal of impeding the infiltration of peripheral inflammation into the central nervous system. MATERIALS AND METHODS: Lipolysaccharide (LPS) was administered intraperitoneally to mice several times to establish a chronic inflammatory model. A cellular inflammatory model was established by LPS in human brain microvascular endothelial cells (HBMECs). The mRNA expressions of inflammatory cytokines interleukin-1ß (IL-1ß) and IL-6 were detected by real-time polymerase chain reaction (PCR). Immunofluorescence staining of platelet endothelial cell adhesion molecule-1 (CD31) and alpha smooth muscle actin (α-SMA) was conducted to assess the level of EndoMT. The expression levels of Occludin, zona occludens protein 1 (ZO-1), Sestrin2, microtubule-associated protein1 light chain 3 (LC3) and inducible nitric oxide synthase (iNOS) were detected by western blotting. RESULTS: LPS treatment induced the downregulation of ZO-1 and Occludin, which was accompanied by the elevated expressions of iNOS, α-SMA, Sestrin2 and LC3-II in the mouse cortex and HBMECs. Mechanistically, the knockdown of Sestrin2 in HBMECs exacerbated the EndoMT induced by LPS treatment, while the overexpression of Sestrin2 inhibited this process. Moreover, the induction of autophagy by rapamycin rescued the EndoMT induced by Sestrin2 knockdown. CONCLUSION: This study revealed that Sestrin2 inhibited endothelial inflammation and EndoMT via enhanced autophagy, which may provide a potential drug target for cerebrovascular inflammatory injury.

LncRNAH19 acts as a ceRNA of let-7 g to facilitate endothelial-to-mesenchymal transition in hypoxic pulmonary hypertension via regulating TGF-ß signalling pathway.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality rates, and the efficiency of current HPH treatment strategies is unsatisfactory. Endothelial-to-mesenchymal transition (EndMT) in the pulmonary artery plays a crucial role in HPH. Previous studies have shown that lncRNA-H19 (H19) is involved in many cardiovascular diseases by regulating cell proliferation and differentiation but the role of H19 in EndMT in HPH has not been defined. METHODS: In this research, the expression of H19 was investigated in PAH human patients and rat models. Then, we established a hypoxia-induced HPH rat model to evaluate H19 function in HPH by Echocardiography and hemodynamic measurements. Moreover, luciferase reporter gene detection, and western blotting were used to explore the mechanism of H19. RESULTS: Here, we first found that the expression of H19 was significantly increased in the endodermis of pulmonary arteries and that H19 deficiency obviously ameliorated pulmonary vascular remodelling and right heart failure in HPH rats, and these effects were associated with inhibition of EndMT. Moreover, an analysis of luciferase activity indicated that microRNA-let-7 g (let-7 g) was a direct target of H19. H19 deficiency or let-7 g overexpression can markedly downregulate the expression of TGFßR1, a novel target gene of let-7 g. Furthermore, inhibition of TGFßR1 induced similar effects to H19 deficiency. CONCLUSIONS: In summary, our findings demonstrate that the H19/let-7 g/TGFßR1 axis is crucial in the pathogenesis of HPH by stimulating EndMT. Our study may provide new ideas for further research on HPH therapy in the near future.

Circ_0000099/miR-223-3p/CTGF Regulates the Growth, Metastasis, and EMT Processes in TGF-ß2-Stimulated Human Lens Epithelial Cells.

PURPOSE: Posterior capsule opacification (PCO) is the major complication of visual impairment after cataract surgery. Circular RNAs (circRNAs) are involved in the development of many diseases. The purpose of this study was to explore the role and molecular mechanism of circ_0000099 in PCO. METHODS: SRA01/04 cells were treated with TGF-ß2 to establish a PCO cell model. The expression of circ_0000099, miR-223-3p, and connective tissue growth factor (CTGF) mRNA was determined by real-time quantitative polymerase chain reaction (qRT-PCR). Western blot assay was used to analyze the protein expression. Cell proliferation, migration, and invasion were analyzed by (4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2 '-Deoxyuridine (EdU), transwell, and wound healing tests. The circ_0000099/miR-223-3p/CTGF relationship was verified by dual luciferase reporter gene and RNA binding protein immunoprecipitation (RIP) assays. RESULTS: TGF-ß2 treatment promoted SRA01/04 cell proliferation invasion, migration, and EMT. Circ_0000099 expression was increased in POC patients and TGF-ß2-treated SRA01/04 cells.Knockdown of circ_0000099 suppressed TGF-ß2-induced proliferation, invasion, migration, and EMT in SRA01/04 cells. miR-223-3p was identified as the target of circ_0000099, and miR-223-3p inhibitor might partly abolish the repression of circ_0000099 silencing on TGF-ß2-triggered SRA01/04 cell disorders. MiR-223-3p directly targeted CTGF. Knockdown of CTGF suppressed TGF-ß2-induced SRA01/04 cell injury. Circ_0000099 can regulate CTGF expression by targeting miR-223-3p. CONCLUSIONS: Circ_0000099 silencing might relieve TGF-2-induced SRA01/04 cell injury by the miR-223-3p/CTGF axis, providing new avenues for the prevention and treatment of PCO.

Targeting lysyl oxidase like 2 attenuates OVA-induced airway remodeling partly via the AKT signaling pathway.

BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.

Suppression of the Epithelial-Mesenchymal Transition and Maintenance of the Liver Functions in Primary Hepatocytes through Dispersion Culture within a Dome-Shaped Collagen Matrix.

Primary hepatocytes are valuable for studying liver diseases, drug-induced liver injury, and drug metabolism. However, when cultured in a two-dimensional (2D) environment, primary hepatocytes undergo rapid dedifferentiation via an epithelial-mesenchymal transition (EMT) and lose their liver-specific functions. On the other hand, a three-dimensional (3D) culture of primary hepatocyte organoids presents challenges for analyzing cellular functions and molecular behaviors due to strong cell-cell adhesion among heterogeneous cells. In this study, we developed a novel dispersion culture method of hepatocytes within a dome-shaped collagen matrix, overcoming conventional limitations. The expression levels of EMT-related genes were lower in rat primary hepatocytes cultured using this method for 4 d than in cells cultured using the 2D method. Furthermore, albumin production, a marker of liver function, declined sharply in rat primary hepatocytes cultured in two dimensions from 6.40 µg/mL/48 h on day 4 to 1.35 µg/mL/48 h on day 8, and declined gradually from 4.92 µg/mL/48 h on day 8 to 3.89 µg/mL/48 h on day 14 in rat primary hepatocytes cultured using our new method. These findings indicate that the newly developed culture method can suppress EMT and maintain liver functions for 14 d in rat primary hepatocytes, potentially expanding the utility of primary hepatocyte cultured by using conventional 3D methods.

INPP4B suppresses HER2-induced mesenchymal transition in HER2+ breast cancer and enhances sensitivity to Lapatinib.

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) tends to metastasize and has a bad prognosis due to its high malignancy and rapid progression. Inositol polyphosphate 4-phosphatase isoenzymes type II (INPP4B) plays unequal roles in the development of various cancers. However, the function of INPP4B in HER2+ BC has not been elucidated. Here we found that INPP4B expression was significantly lower in HER2+ BC and positively correlated with the prognosis by bioinformatics and tissue immunofluorescence analyses. Overexpression of INPP4B inhibited cell proliferation, migration, and growth of xenografts in HER2+ BC cells. Conversely, depletion of INPP4B reversed these effects and activated the PDK1/AKT and Wnt/ß-catenin signaling pathways to promote epithelial-mesenchymal transition (EMT) progression. Moreover, INPP4B overexpression blocked epidermal growth factor (EGF) -induced cell proliferation, migration and EMT progression, whereas INPP4B depletion antagonized HER2 depletion in reduction of cell proliferation and migration of HER2+ BC cells. Additionally, Lapatinib (LAP) inhibited HER2+ BC cell survival, proliferation and migration, and its effect was further enhanced by overexpression of INPP4B. In summary, our results illustrate that INPP4B suppresses HER2+ BC growth, migration and EMT, and its expression level affects patient outcome, further providing new insights into clinical practice.

The multifaceted role of SOX2 in breast and lung cancer dynamics.

Breast and lung cancers are leading causes of death among patients, with their global mortality and morbidity rates increasing. Conventional treatments often prove inadequate due to resistance development. The alteration of molecular interactions may accelerate cancer progression and treatment resistance. SOX2, known for its abnormal expression in various human cancers, can either accelerate or impede cancer progression. This review focuses on examining the role of SOX2 in breast and lung cancer development. An imbalance in SOX2 expression can promote the growth and dissemination of these cancers. SOX2 can also block programmed cell death, affecting autophagy and other cell death mechanisms. It plays a significant role in cancer metastasis, mainly by regulating the epithelial-to-mesenchymal transition (EMT). Additionally, an imbalanced SOX2 expression can cause resistance to chemotherapy and radiation therapy in these cancers. Genetic and epigenetic factors may affect SOX2 levels. Pharmacologically targeting SOX2 could improve the effectiveness of breast and lung cancer treatments.

Epithelial mesenchymal transition in human menstruation and implantation.

The endometrium during the sexual cycle undergoes detachment, tissue remodeling, and differentiation during the menstrual cycle. Localized and transient destruction and regeneration of endometrial tissue are also essential for pregnancy. It is possible to attribute many causes of failure in infertility treatment to the implantation stage. To improve the success rate of plateau fertility treatment, it is important to understand the regeneration mechanism of the endometrium, a unique regenerative tissue in the human body. In association with cell proliferation, tissue remodeling requires the relocation of proliferative cells, and the steady-state epithelial cells need to be motile for the relocation. Transient add-on motile activity in epithelial cells is mediated by epithelial to mesenchymal transition (EMT) and reversible mesenchymal to epithelial transition (MET). The destruction and regeneration of endometrial tissue over a period of days to weeks requires a system with a rapid and characteristic mechanism similar to that of wound healing. Here, I review the relationship between the well-known phenomenon of EMT in wound healing and endometrial tissue remodeling during the sexual cycle and pregnancy establishment, which are automatically triggered by menstruation and embryonal invasion.

Enhydrin suppresses the malignant phenotype of GBM via Jun/Smad7/TGF-ß1 signaling pathway.

GBM is the most threatening form of brain tumor. The advancement of GBM is propelled by the growth, infiltration, and movement of cancer cells. Understanding the underlying mechanisms and identifying new therapeutic agents are crucial for effective GBM treatment. Our research focused on examining the withhold influence of Enhydrin on the destructive activity of GBM cells, both in laboratory settings and within living organisms. By employing network pharmacology and bioinformatics analysis, we have determined that Jun serves as the gene of interest, and EMT as the critical signaling pathway. Mechanistically, Enhydrin inhibits the activity of the target gene Jun to increase the expression of Smad7, which is infinitively regulated by the transcription factor Jun, and as the inhibitory transcription factor, Smad7 can down-regulate TGF-ß1 and the subsequent Smad2/3 signaling pathway. Consequently, this whole process greatly hinders the EMT mechanism of GBM, leading to the notable decline in cell proliferation, invasion, and migration. In summary, our research shows that Enhydrin hinders EMT by focusing on the Jun/Smad7/TGF-ß1 signaling pathway, presenting a promising target for treating GBM. Moreover, Enhydrin demonstrates encouraging prospects as a new medication for GBM treatment.

A computational analysis of the role of integrins and Rho-GTPases in the emergence and disruption of apical-basal polarization in renal epithelial cells.

Apical-basal polarization in renal epithelial cells is crucial to renal function and an important trigger for tubule formation in kidney development. Loss of polarity can induce epithelial-to-mesenchymal transition (EMT), which can lead to kidney pathologies. Understanding the relative and combined roles of the involved proteins and their interactions that govern epithelial polarity may provide insights for controlling the process of polarization via chemical or mechanical manipulations in an in vitro or in vivo setting. Here, we developed a computational framework that integrates several known interactions between integrins, Rho-GTPases Rho, Rac and Cdc42, and polarity complexes Par and Scribble, to study their mutual roles in the emergence of polarization. The modeled protein interactions were shown to induce the emergence of polarized distributions of Rho-GTPases, which in turn led to the accumulation of apical and basal polarity complexes Par and Scribble at their respective poles, effectively recapitulating polarization. Our multiparametric sensitivity analysis suggested that polarization depends foremost on the mutual inhibition between Rac and Rho. Next, we used the computational framework to investigate the role of integrins and GTPases in the generation and disruption of polarization. We found that a minimum concentration of integrins is required to catalyze the process of polarization. Furthermore, loss of polarization was found to be only inducible via complete degradation of the Rho-GTPases Rho and Cdc42, suggesting that polarization is fairly stable once it is established. Comparison of our computational predictions against data from in vitro experiments in which we induced EMT in renal epithelial cells while quantifying the relative Rho-GTPase levels, displayed that EMT coincides with a large reduction in the Rho-GTPase Rho. Collectively, these results demonstrate the essential roles of integrins and Rho-GTPases in the establishment and disruption of apical-basal polarity and thereby provide handles for the in vitro or in vivo regulation of polarity.

Reflections on the complex mechanisms of endometriosis from the perspective of ferroptosis.

Ferroptosis is a novel type of iron-dependent programmed cell death characterised by intracellular iron overload, increased lipid peroxidation and abnormal accumulation of reactive oxygen species.It has been implicated in the progression of several diseases including cancer, ischaemia-reperfusion injury, neurodegenerative diseases and liver disease. The etiology of endometriosis (EMS) is still unclear and is associated with multiple factors, often accompanied by various forms of cell death and a complex microenvironment. In recent decades, the role of non-traditional forms of cell death, represented by ferroptosis, in endometriosis has come to the attention of researchers. This article reviews the transitional role of iron homeostasis in the development of ferroptosis, the characteristics and regulatory mechanisms of ferroptosis, and focuses on summarising the links between iron death and various pathogenic mechanisms of EMS, including oxidative stress, dysregulation of lipid metabolism, inflammation, autophagy and epithelial-mesenchymal transition. The possible applications of ferroptosis in the treatment of EMS, future research directions and current issues are discussed with the aim of providing new ideas for further understanding of EMS.

P4HA2 contributes to head and neck squamous cell carcinoma progression and EMT through PI3K/AKT signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) can be defined as a deadly illness with a dismal prognosis in advanced stages. Therefore, we seek to examine P4HA2 expression and effect in HNSCC, along with the underlying mechanisms. This study utilized integrated bioinformatics analyses to evaluate the P4HA2 expression pattern, prognostic implication, and probable function in HNSCC. The study conducted various in vitro experiments, including colony formation, CCK-8, flow cytometry, wound healing, and transwell assays, on the human HNSCC cell line CAL-27 to examine the involvement of P4HA2 in HNSCC progression. Moreover, western blotting was used to investigate epithelial-mesenchymal transition (EMT) markers and PI3K/AKT pathway markers to elucidate the underlying mechanisms. P4HA2 expression was significantly enhanced in HNSCC, and its overexpression was correlated to tumor aggressiveness and a poor prognosis in patients. Based on in vitro experiments, the overexpressed P4HA2 enhanced cell proliferation, migration, invasion, as well as EMT while reducing apoptosis, whereas P4HA2 silencing exhibited the reverse effect. P4HA2 overexpression enhanced PI3K/AKT phosphorylation in HNSCC cells. Moreover, LY294002 was observed to counteract the effects of upregulated P4HA2 on proliferation, migration, invasion, and EMT in HNSCC. Collectively, we indicated that P4HA2 promoted HNSCC progression and EMT via PI3K/AKT signaling pathway.

CLIC4 Function in the Epithelial-Mesenchymal Transition of Epithelial Odontogenic Lesions.

BACKGROUND: Odontogenic lesions constitute a heterogeneous group of lesions. CLIC4 protein regulates different cellular processes, including epithelial-mesenchymal transition and fibroblast-myofibroblast transdifferentiation. This study analyzed CLIC4, E-cadherin, Vimentin, and α-SMA immunoexpression in epithelial odontogenic lesions that exhibit different biological behavior. METHODS: It analyzed the immunoexpression of CLIC4, E-cadherin, and Vimentin in the epithelial cells, as well as CLIC4 and α-SMA in the mesenchymal cells, of ameloblastoma (AM) (n = 16), odontogenic keratocyst (OKC) (n = 20), and adenomatoid odontogenic tumor (AOT) (n = 8). Immunoexpressions were categorized as score 0 (0% positive cells), 1 (< 25%), 2 (≥ 25% - < 50%), 3 (≥ 50% - < 75%), or 4 (≥ 75%). RESULTS: Cytoplasmic CLIC4 immunoexpression was higher in AM and AOT (p < 0.001) epithelial cells. Nuclear-cytoplasmic CLIC4 was higher in OKC's epithelial lining (p < 0.001). Membrane (p = 0.012) and membrane-cytoplasmic (p < 0.001) E-cadherin immunoexpression were higher in OKC, while cytoplasmic E-cadherin expression was higher in AM and AOT (p < 0.001). Vimentin immunoexpression was higher in AM and AOT (p < 0.001). Stromal CLIC4 was higher in AM and OKC (p = 0.008). Similarly, α-SMA immunoexpression was higher in AM and OKC (p = 0.037). Correlations in these proteins' immunoexpression were observed in AM and OKC (p < 0.05). CONCLUSIONS: CLIC4 seems to regulate the epithelial-mesenchymal transition, modifying E-cadherin and Vimentin expression. In mesenchymal cells, CLIC4 may play a role in fibroblast-myofibroblast transdifferentiation. CLIC4 may be associated with epithelial odontogenic lesions with aggressive biological behavior.