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Prostate cancer (PCa) poses a significant challenge because of the difficulty in identifying aggressive tumors, leading to overtreatment and missed personalized therapies. Although only 8% of cases progress beyond the prostate, the accurate prediction of aggressiveness remains crucial. Thus, this study focused on studying retinoblastoma phosphorylated at Serine 249 (Phospho-Rb S249), N-cadherin, β-catenin, and E-cadherin as biomarkers for identifying aggressive PCa using a logistic regression model and a classification and regression tree (CART). Using immunohistochemistry (IHC), we targeted the expression of these biomarkers in PCa tissues and correlated their expression with clinicopathological data of the tumor. The results showed a negative correlation between E-cadherin and β-catenin with aggressive tumor behavior, whereas Phospho-Rb S249 and N-cadherin positively correlated with increased tumor aggressiveness. Furthermore, patients were stratified based on Gleason scores and E-cadherin staining patterns to evaluate their capability for early identification of aggressive PCa. Our findings suggest that the classification tree is the most effective method for measuring the utility of these biomarkers in clinical practice, incorporating β-catenin, tumor grade, and Gleason grade as relevant determinants for identifying patients with Gleason scores ≥ 4 + 3. This study could potentially benefit patients with aggressive PCa by enabling early disease detection and closer monitoring. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic prostate cancer (mPCa) is a leading cause of death primarily due to its resistance to treatments like enzalutamide. This study investigates how the protein HMGA2 contributes to this resistance. We found that cancer cells with high levels of HMGA2 became less sensitive to enzalutamide but not to another drug, alisertib. Interestingly, although these cells resisted enzalutamide, they did not show changes in a key prostate cancer protein called AR. Furthermore, a knockdown of HMGA2 sensitized the cells to both drugs. Clinically, 3% of patients showed changes in HMGA2, which were more common in cancers that had metastasized to bones, lymph nodes, and the liver. Our research suggests that HMGA2 could be used as a marker to predict enzalutamide resistance in mPCa cells. Additionally, alisertib may be an effective treatment for patients with high HMGA2 levels, offering a new potential therapeutic strategy for managing metastatic prostate cancer. Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial–mesenchymal transition (EMT). This study examines HMGA2's role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2. [ABSTRACT FROM AUTHOR]

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta‐analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA‐MB‐231) with sodium L‐lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L‐lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings. [ABSTRACT FROM AUTHOR]

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase and is characteristically downregulated in metastatic cancer. Several studies showed that DAPK1 is involved in both the early and late stages of cancer. DAPK1 downregulation is elaborately controlled by epigenetic, transcriptional, posttranscriptional, and posttranslational processes. DAPK1 is known to regulate not only cancer cells but also stromal cells. Recent studies showed that DAPK1 was involved not only in tumor suppression but also in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in colon and thyroid cancers. CSCs are major factors in determining cancer aggressiveness in cancer metastasis and treatment prognosis by influencing EMT. However, the molecular mechanism involved in the regulation of cancer cells by DAPK1 remains unclear. In particular, little is known about the existence of CSCs and how they are regulated in papillary thyroid carcinoma (PTC) among thyroid cancers. In this review, we describe the molecular mechanism of CSC regulation by DAPK1 in PTC progression.

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.

High-risk human papillomavirus (HR-HPV; HPV-16) and cigarette smoking are associated with cervical cancer (CC); however, the underlying mechanism(s) remain unclear. Additionally, the carcinogenic components of tobacco have been found in the cervical mucus of women smokers. Here, we determined the effects of cigarette smoke condensate (CSC; 3R4F) on human ectocervical cells (HPV-16 Ect/E6E7) exposed to CSC at various concentrations (10−6–100 μg/mL). We found CSC (10−3 or 10 μg/mL)-induced proliferation, enhanced migration, and histologic and electron microscopic changes consistent with EMT in ectocervical cells with a significant reduction in E-cadherin and an increase in the vimentin expression compared to controls at 72 h. There was increased phosphorylation of receptor tyrosine kinases (RTKs), including Eph receptors, FGFR, PDGFRA/B, and DDR2, with downstream Ras/MAPK/ERK1/2 activation and upregulation of common EMT-related genes, TGFB SNAI2, PDGFRB, and SMAD2. Our study demonstrated that CSC induces EMT in ectocervical cells with the upregulation of EMT-related genes, expression of protein biomarkers, and activation of RTKs that regulate TGFB expression, and other EMT-related genes. Understanding the molecular pathways and environmental factors that initiate EMT in ectocervical cells will help delineate molecular targets for intervention and define the role of EMT in the initiation and progression of cervical intraepithelial neoplasia and CC. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pancreatic ductal adenocarcinoma (PDAC). There are insufficient and contradictory data in the scientific literature on the peculiarities of epithelial and mesenchymal marker expression in PDAC ducts and EMT zone, which requires further research on the role of EMT in the development and progression of PDAC. Aim: to conduct a comprehensive assessment of epithelial and mesenchymal markers of EMT in the PDAC ducts and EMT zone at different degrees of differentiation. Materials and methods. A comprehensive pathomorphological and immunohistochemical examination including 49 cases of surgical material from patients with PDAC, divided into groups of moderate (G2) and low degree of tumor differentiation (G3). Results. PDAC was characterized by low levels of E-cadherin expression in both ducts and EMT – Me = 22.58 % [12.81; 36.23] and Me = 25.17 % [19.04; 35.37], respectively (p > 0.05). Only membrane expression of the marker was detected in the ducts and membrane-cytoplasmic one – in the EMT zone without significant differences in the groups. There was a significant decrease in the ductal β-catenin expression (p < 0.05) in G2 with membrane-cytoplasmic staining (Me = 15.58 % [10.42; 26.24]), in G3 – with membrane (Me = 4.42 % [2.35; 5.93]); in the EMT zone, only membrane-cytoplasmic expression was observed in both groups without significant difference (p > 0.05). Membrane expression of CK7 was positive in 100 % of PDAC, significantly lower at G2 (Me = 19.51 % [10.70; 27.24]; Me = 26.19 % [20.93; 30.05], p < 0.05), and CK18 (Me = 21.34 % [9.68; 29.96] – in G2, in G3 – Me = 22.50 % [8.24; 40.08], p > 0.05). Expression of α-SMA and Vim was seen in spindle-shaped stromal cells, around tubular and trabecular structures with membrane-cytoplasmic staining. There was no significant difference between α-SMA in G2 and G3, the level of vimentin was significantly lower in G3 (p < 0.05). Conclusions. The features of PDAC E-cadherin, β-catenin, CK7 and CK18 marker expression indicate a greater EMT process at the periphery of the tumor and its severity increases with tumor progression. The optimal markers to determine the mesenchymal phenotype of PDAC cells are α-SMA and vimentin.

The epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pancreatic ductal adenocarcinoma (PDAC). There are insufficient and contradictory data in the scientific literature on the peculiarities of epithelial and mesenchymal marker expression in PDAC ducts and EMT zone, which requires further research on the role of EMT in the development and progression of PDAC. Aim: to conduct a comprehensive assessment of epithelial and mesenchymal markers of EMT in the PDAC ducts and EMT zone at different degrees of differentiation. Materials and methods. A comprehensive pathomorphological and immunohistochemical examination including 49 cases of surgical material from patients with PDAC, divided into groups of moderate (G2) and low degree of tumor differentiation (G3). Results. PDAC was characterized by low levels of E-cadherin expression in both ducts and EMT -- Me = 22.58 % [12.81; 36.23] and Me = 25.17 % [19.04; 35.37], respectively (p > 0.05). Only membrane expression of the marker was detected in the ducts and membrane- cytoplasmic one -- in the EMT zone without significant differences in the groups. There was a significant decrease in the ductal β-catenin expression (p < 0.05) in G2 with membrane-cytoplasmic staining (Me = 15.58 % [10.42; 26.24]), in G3 -- with membrane (Me = 4.42 % [2.35; 5.93]); in the EMT zone, only membrane-cytoplasmic expression was observed in both groups without significant difference (p > 0.05). Membrane expression of CK7 was positive in 100 % of PDAC, significantly lower at G2 (Me = 19.51 % [10.70; 27.24]; Me = 26.19 % [20.93; 30.05], p < 0.05), and CK18 (Me = 21.34 % [9.68; 29.96] -- in G2, in G3 -- Me = 22.50 % [8.24; 40.08], p > 0.05). Expression of α-SMA and Vim was seen in spindle-shaped stromal cells, around tubular and trabecular structures with membrane- cytoplasmic staining. There was no significant difference between α-SMA in G2 and G3, the level of vimentin was significantly lower in G3 (p < 0.05). Conclusions. The features of PDAC E-cadherin, β-catenin, CK7 and CK18 marker expression indicate a greater EMT process at the periphery of the tumor and its severity increases with tumor progression. The optimal markers to determine the mesenchymal phenotype of PDAC cells are α-SMA and vimentin. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis B virus X protein (HBx) play a key role in pathogenesis of HBV-induced hepatocellular carcinoma (HCC) by promoting epithelial to mesenchymal transition (EMT). In this study, we hypothesized that inhibition of HBx is an effective strategy to combat HCC. Methodology and Results: We designed and synthesized novel HBx gene specific single guide RNA (sgRNA) with CRISPR/Cas9 system and studied its in vitro effects on tumour properties of HepG2-2.15. Full length HBx gene was excised using HBx-CRISPR that resulted in significant knockdown of HBx expression in hepatoma cells. HBx-CRISPR also decreased levels of HBsAg and HBV cccDNA expression. A decreased expression of mesenchymal markers, proliferation and tumorigenic properties was observed in HBx-CRISPR treated cells as compared to controls in both twoand three- dimensional (2D and 3D) tumour models. Transcriptomics data showed that out of 1159 differentially expressed genes in HBx-CRISPR transfected cells as compared to controls, 70 genes were upregulated while 1089 genes associated with cell proliferation and EMT pathways were downregulated. Conclusion: Thus, targeting of HBx by CRISPR/Cas9 gene editing system reduces covalently closed circular DNA (cccDNA) levels, HBsAg production and mesenchymal characteristics of HBV-HCC cells. We envision inhibition of HBx by CRISPR as a novel therapeutic approach for HBV-induced HCC. [ABSTRACT FROM AUTHOR]

High-risk human papillomavirus (HR-HPV; HPV-16) and cigarette smoking are associated with cervical cancer (CC); however, the underlying mechanism(s) remain unclear. Additionally, the carcinogenic components of tobacco have been found in the cervical mucus of women smokers. Here, we determined the effects of cigarette smoke condensate (CSC; 3R4F) on human ectocervical cells (HPV-16 Ect/E6E7) exposed to CSC at various concentrations (10−6–100 μg/mL). We found CSC (10−3 or 10 μg/mL)-induced proliferation, enhanced migration, and histologic and electron microscopic changes consistent with EMT in ectocervical cells with a significant reduction in E-cadherin and an increase in the vimentin expression compared to controls at 72 h. There was increased phosphorylation of receptor tyrosine kinases (RTKs), including Eph receptors, FGFR, PDGFRA/B, and DDR2, with downstream Ras/MAPK/ERK1/2 activation and upregulation of common EMT-related genes, TGFB SNAI2, PDGFRB, and SMAD2. Our study demonstrated that CSC induces EMT in ectocervical cells with the upregulation of EMT-related genes, expression of protein biomarkers, and activation of RTKs that regulate TGFB expression, and other EMT-related genes. Understanding the molecular pathways and environmental factors that initiate EMT in ectocervical cells will help delineate molecular targets for intervention and define the role of EMT in the initiation and progression of cervical intraepithelial neoplasia and CC.

The complex process known as epithelial to mesenchymal transition (EMT) plays a fundamental role in several biological settings, encompassing embryonic development, wound healing, and pathological conditions such as cancer and fibrosis. In recent years, a bulk of research has brought to light the key role of copper, a trace element with essential functions in cellular metabolism, cancer initiation and progression. Indeed, copper, besides functioning as cofactor of enzymes required for essential cellular processes, such as energy production and oxidation reactions, has emerged as an allosteric regulator of kinases whose activity is required to fulfill cancer dissemination through the EMT. In this comprehensive review, we try to describe the intricate relationship between the transition metal copper and EMT, spanning from the earliest foundational studies to the latest advancements. Our aim is to shed light on the multifaceted roles undertaken by copper in EMT in cancer and to unveil the diverse mechanisms by which copper homeostasis exerts its influence over EMT regulators, signaling pathways, cell metabolic reprogramming and transcription factors ultimately contributing to the spread of cancer. Therefore, this review not only may contribute to a deeper comprehension of copper-mediated mechanisms in EMT but also supports the hypothesis that targeting copper may contribute to counteract the progression of EMT-associated pathologies. [Display omitted] [ABSTRACT FROM AUTHOR]

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.

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca 2+ /CaM)-dependent serine/threonine (Ser/Thr) protein kinase and is characteristically downregulated in metastatic cancer. Several studies showed that DAPK1 is involved in both the early and late stages of cancer. DAPK1 downregulation is elaborately controlled by epigenetic, transcriptional, posttranscriptional, and posttranslational processes. DAPK1 is known to regulate not only cancer cells but also stromal cells. Recent studies showed that DAPK1 was involved not only in tumor suppression but also in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in colon and thyroid cancers. CSCs are major factors in determining cancer aggressiveness in cancer metastasis and treatment prognosis by influencing EMT. However, the molecular mechanism involved in the regulation of cancer cells by DAPK1 remains unclear. In particular, little is known about the existence of CSCs and how they are regulated in papillary thyroid carcinoma (PTC) among thyroid cancers. In this review, we describe the molecular mechanism of CSC regulation by DAPK1 in PTC progression.