Epithelial-mesenchymal Transition Research Articles

CAF-derived miR-642a-3p supports migration, invasion, and EMT of hepatocellular carcinoma cells by targeting SERPINE1

Background Cancer-associated fibroblasts (CAFs) and hepatocellular carcinoma (HCC) cells interact to promote HCC progression, but the underlying mechanisms remain unclear. Serpin family E member 1 (SERPINE1) has conflicting roles in HCC, and microRNAs (miRNAs) are known to regulate tumor progression through intercellular communication. Therefore, we investigated the potential involvement of miRNA/SERPINE1 axis in crosstalk between CAFs and HCC cells. Methods In this study, candidate miRNAs targeting SERPINE1 3′ UTR were predicted using multiple miRNA databases. The miRNAs and SERPINE1 mRNA expression in Huh7 cells was assessed after co-culture with CAFs using RT-qPCR. Huh7 cell proliferation and invasion were detected after SERPINE1 siRNA. The functions of the CAF-derived miR-642a-3p/SERPINE1 axis in HCC cells were examined using CCK-8, wound healing, transwell assays, western blot, and dual-luciferase reporter assays. Moreover, a orthotopic xenograft model was used to investigate the contribution of miR-642a-3p knockdown in HCC. Results SERPINE1 mRNA expression decreased, while miR-642a-3p expression increased in Huh7 cells co-cultured with CAFs. SERPINE1 knockdown enhanced Huh7 cell proliferation and invasion as well as miR-642a-3p expression. miR-642a-3p overexpression promoted migration, invasion, and epithelial-mesenchymal transition (EMT) in Huh7 cells by targeting SERPINE1, while miR-642a-3p knockdown yielded the opposite effect. Rescue experiments confirmed that SERPINE1 knockdown attenuated the inhibitory effects of miR-642a-3p knockdown on migration, invasion, and EMT in Huh7 cells. Importantly, miR-642a-3p knockdown suppressed growth and EMT in orthotopic liver tumors. Conclusion CAF-derived miR-642a-3p/SERPINE1 axis facilitated migration, invasion, and EMT in the HCC cells, suggesting miR-642a-3p/SERPINE1 axis can be a potential therapeutic target for HCC.

EXTH-78. A NOVEL BISPECIFIC S100A4/TFR ANTIBODY TO REPROGRAM THE GLIOMA TUMOR MICROENVIRONMENT AND TARGET GLIOMA STEM CELLS

Abstract GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. While immunotherapy is a promising treatment modality for GBM, most clinical trials have thus far only provided a modest benefit to GBM patients. We propose that enhancing the efficacy of immunotherapy for GBM requires approaches that increase T cell infiltration and reprogram the myeloid cells to a more pro-inflammatory state. S100A4 is a major regulator of stemness, epithelial-mesenchymal transition, and a critical regulator of immune suppressive myeloid and T cell phenotypes in GBM. Targeting S100A4 in either glioma or stromal cells is sufficient to reprogram the tumor immune landscape and extend survival of glioma bearing mice, indicating that S100A4 is a promising immunotherapy target. We recently developed a S100A4 blocking monoclonal antibody; however, this antibody does not cross the blood brain barrier (BBB) efficiently to confer significant therapeutic benefit, limiting its efficacy in treating GBM. To overcome this challenge, we generated a bispecific S100A4-TfR antibody (BsA) that allows robust BBB penetration, and tested this in a pre-clinical syngeneic, orthotopic mouse model of GBM. Using ELISA, confocal immunofluorescent microscopy, flow cytometry, and bulk RNA sequencing, we report that systemic administration of the S100A4-TfR BsA results in increased immune cell infiltration with a preferential increase in CD4 T cell infiltration, and potent immune remodeling of the tumor microenvironment to a more pro-inflammatory state. Furthermore, the BsA is taken up by glioma cells intracellularly, which is correlated with depletion of intracellular S100A4 and decreased nuclear SOX2 localization, which would reduce stemness of glioma cells. Functionally, in vitro BsA treatment of primary glioma cell cultures shows decreased S100A4 expression, proliferation, and self-renewal. Our results suggest that S100A4-TfR BsA is a novel dual activity inhibitor to simultaneously reprogram the GBM immune landscape and reduce glioma stemness.

Establishment and characterization of mouse metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma organoids

Metabolic dysfunction-associated steatohepatitis (MASH) is a form of chronic liver inflammation associated with metabolic syndrome, such as obesity and a major cause of hepatocellular carcinoma (HCC). Multi-biotics, a soymilk fermented with lactic acid bacteria, are known to alleviate obesity by lowering lipid profile. This study aimed to establish and characterize mouse organoids derived from MASH-related HCC models to evaluate drug responses, particularly focusing on Lenvatinib resistance. Organoids were developed using mouse liver tissues subjected to a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) to mimic MASH-related HCC. The study evaluated the effect of multi-biotics, a fermented product, on tumor regression and drug sensitivity. While multi-biotics did not reduce tumor burden, they enhanced the response to Lenvatinib. Additionally, repeated treatment with Lenvatinib led to the development of drug-resistant organoids. Transcriptomic analysis of these resistant organoids identified key pathways related to KRAS signaling, inflammation, and epithelial-mesenchymal transition (EMT), revealing potential targets for overcoming Lenvatinib resistance. This study provides valuable insights into MASH-related HCC progression and drug resistance, offering a model for further therapeutic research.

ALKBH5 activates CEP55 transcription through m6A demethylation in FOXP2 mRNA and expedites cell cycle entry and EMT in ovarian cancer

BackgroundCentrosomal protein of 55 kDa (CEP55) overexpression has been linked to tumor stage, aggressiveness of the tumor, poor prognosis, and metastasis. This study aims to elucidate the action of CEP55 in ovarian cancer (OC) and the regulation by the alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5)/Forkhead box protein P2 (FOXP2) axis.MethodsDifferentially expressed genes in OC were identified using in silico identification, followed by prognostic value assessment. Lentiviral vectors were constructed to downregulate CEP55 in OC cells, and colony formation, EdU, TUNEL, flow cytometry, Transwell assays, and Phalloidin staining were conducted. Transcription factors regulating CEP55 were predicted and verified, and rescue experiments were performed. The effect of ALKBH5-mediated demethylation on FOXP2 mRNA stability and OC cell cycle and EMT were analyzed.ResultsHigh expression of CEP55 in OC was linked to unsatisfactory prognosis of patients. Knockdown of CEP55 repressed proliferation, invasiveness, and epithelial-mesenchymal transition (EMT) while inducing apoptosis and cell cycle arrest in OC cells. FOXP2 bound to the promoter of CEP55 to repress CEP55 transcription. FOXP2 regulated transcriptional repression of CEP55 to impede the malignant progression of OC and inhibit tumor metastasis. ALKBH5-mediated demethylation modification induced mRNA degradation of FOXP2. Knockdown of ALKBH5 induced cell cycle arrest and inhibited EMT in OC cells.ConclusionsALKBH5 hinders FOXP2-mediated transcriptional repression of CEP55 to promote the malignant progression of OC via cell cycle and EMT.

N-acetylglucosaminyltransferase V drives colorectal cancer metastasis by facilitating ZO-1 ubiquitination and degradation

Increasing evidence supports the crucial role of Epithelial-Mesenchymal Transition (EMT) in cancer invasion and metastasis. N-acetylglucosaminyltransferase V (MGAT5), which is associated with multiantenna glycosylation, can contribute to tumorigenesis, yet its specific role in promoting colorectal cancer (CRC) metastasis remains unclear. Bioinformatics analysis of CRC datasets revealed that elevated MGAT5 expression was associated with EMT and a poor prognosis. In vitro experiments confirmed the pivotal role of MGAT5 as an EMT regulator in CRC cells. MGAT5 overexpression stimulated cell proliferation and migration, while MGAT5 knockdown had the opposite effect. Mechanistically, MGAT5 promoted EMT through multiantenna glycosylation of ZO-1, promoting its ubiquitination and reducing its expression. Clinically, MGAT5 upregulation in the CRC TMA correlated negatively with ZO-1 expression, which is indicative of malignancy and a poor prognosis. This study revealed that MGAT5 promotes EMT in CRC via interactions between multiple antenna glycosylation products and ZO-1 ubiquitination/degradation, indicating that MGAT5 could serve as a promising therapeutic target for CRC.Graphical

Association Between Phosphorylated AXL Expression and Survival in Patients with Gastric Cancer

Background: Gastric cancer (GC) is a leading cause of cancer-related mortality, particularly in East Asia. Despite treatment advances, the prognosis remains poor owing to late diagnosis and high metastatic potential. Phosphorylated AXL (pAXL), a receptor tyrosine kinase, promotes cancer progression, including epithelial–mesenchymal transition (EMT), tumor growth, and metastasis. In this study, we aimed to investigate the relationship between pAXL expression and prognosis in patients with GC, focusing on survival outcomes and other biomarkers such as fibronectin and phosphorylated AKT (pAkt). Methods: Immunohistochemistry was performed to assess the expression of pAXL, fibronectin, and pAkt in 188 GC specimens collected between 2000 and 2013. H-scores were calculated based on staining intensity and percentage. The association between pAXL expression and patient outcomes was assessed using Kaplan–Meier survival analysis and multivariate logistic regression. Results: Higher pAXL expression was significantly associated with improved survival, particularly in male patients. pAXL expression positively correlated with fibronectin and pAkt upregulation, suggesting its role in promoting tumor invasion and EMT. Multivariate analysis identified pAXL, fibronectin, and pAkt as significant prognostic indicators, whereas other factors such as age, tumor grade, and tumor size were not statistically significant. Conclusions: This study identified pAXL as a valuable prognostic marker in GC, with higher expression levels associated with better survival outcomes, particularly in male patients. pAXL enhanced the invasive potential of GC cells through fibronectin and pAkt regulation, making it a promising therapeutic target. Further research is needed to explore the potential of pAXL-targeted therapies and better understand their role in cancer progression and treatment response.

Elevated ITGA3 expression serves as a novel prognostic biomarker and regulates tumor progression in cervical cancer

Patients with advanced and recurrent cervical cancer often lack satisfactory treatment outcomes. Thus, it is necessary to seek reliable biomarkers that provide the ability to identify the disease at an early stage and predict the patient prognosis, providing new strategies for the treatment of cervical cancer. The sequencing data of ITGA3 were retrieved from public datasets. Immune infiltration and sensitivity of potential immunotherapy and chemotherapy have been analyzed between two subgroups. Functional analysis was applied to excavate the related pathways of ITGA3 in cervical cancer. Furthermore, the impact of ITGA3 in tumor progression has been verified in vitro. The results revealed that the level of ITGA3 was upregulated in cervical cancer, and was positively correlated with worse prognosis. The tumor microenvironment of patients in the high-risk group was immunosuppressed. Patients in high-risk group may not benefit from immunotherapy, but be may be sensitive to several chemotherapy drugs. Notably, the angiogenesis, epithelial mesenchymal transition, and PI3K pathway were increased in high-risk group. Collectively, ITGA3 is a marker of poor prognosis and promotes tumor progression by regulating PI3K/AKT pathway in cervical cancer. Our results provide new insights for potential molecular targeted therapy and prognostic prediction of cervical cancer.

Corynoxine suppresses lung adenocarcinoma proliferation and metastasis via inhibiting PI3K/AKT pathway and suppressing Cyclooxygenase-2 expression

BackgroundLung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer.MethodsThe impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice.ResultsIn this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis.ConclusionThis study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD.

New Insights into the Toxic Effects of Different Sizes of Nanosilica Particles in Food on the Mouse Bladder: Involving Epithelial–Mesenchymal Transition

New Insights into the Toxic Effects of Different Sizes of Nanosilica Particles in Food on the Mouse Bladder: Involving Epithelial–Mesenchymal Transition

Alanyl-Glutamine Inhibits the Epithelial-Mesenchymal Transition of Airway Epithelial Cells in Asthmatic Mice via DPP4-SIRT1 Pathway

Introduction: Alanyl-glutamine (Ala-Gln) is a compound known for its protective effects in various tissue injuries. However, its role in asthma-related lung injuries remains underexplored. This study investigates the mechanisms by which Ala-Gln modulates sDPP4-induced airway epithelial-mesenchymal transition and ovalbumin (OVA)-induced asthma in a mouse model. Methods: An asthma model was established in female C57BL/6 J mice by using OVA. CD4+ T cells and bronchial epithelial cells (BECs) were isolated from the spleen and bronchi of the mice, respectively. Interventions included recombinant sCD26/sDPP4 protein, Ala-Gln, and EX527 (a SIRT1 inhibitor). Flow cytometry was used to assess Th17 and Treg cell populations. Mice were treated with Ala-Gln, EX527, and budesonide (BUD). Histopathological changes in lung tissues were evaluated using hematoxylin-eosin and Masson staining. White blood cell counts were measured with a hematology analyzer. The expression levels of DPP4, IL-17, SIRT1, SMAD2/3, N-cadherin, E-cadherin, MMP9, and α-SMA proteins were analyzed. Results: Treatment with recombinant sCD26/sDPP4 resulted in decreased E-cadherin expression in BECs and increased levels of α-SMA, MMP9, and N-cadherin, effects that were mitigated by Ala-Gln. Ala-Gln also prevented the reduction in SIRT1 expression in BECs and the increase in Th17 cell differentiation induced by recombinant sCD26/sDPP4. EX527 administration alongside Ala-Gln reversed these changes and enhanced the phosphorylation of SMAD2/3 through SIRT1 signaling. BUD alone reduced inflammation and fibrosis in bronchial tissue and lowered the Th17/Treg ratio in peribronchial lymph nodes. The therapeutic effect of BUD was further improved with concurrent Ala-Gln treatment. Conclusion: Ala-Gln can inhibit BEC fibrosis and Th17 cell differentiation mediated by recombinant sCD26/sDPP4 through the SIRT1 pathway. Combined with BUD, Ala-Gln enhanced therapeutic efficacy in OVA-induced asthma in mice, which could offer improved outcomes for asthmatic patients with elevated DPP4 levels.

DNA damage-induced EMT controlled by the PARP dependent chromatin remodeler ALC1 promotes DNA repair efficiency through RAD51 in tumor cells.

Epithelial-to-mesenchymal transition (EMT) allows cancer cells to metastasize while acquiring resistance to apoptosis and chemotherapeutic agents with significant implications for patients' prognosis and survival. Despite its clinical relevance, the mechanisms initiating EMT during cancer progression remain poorly understood. We demonstrate that DNA damage triggers EMT and that activation of PARP and the PARP-dependent chromatin remodeler ALC1 (CHD1L) was required for this response. Our results suggest that this activation directly facilitates access to the chromatin of EMT transcriptional factors (TFs) which then initiate cell reprogramming. We also show that EMT-TFs bind to the RAD51 promoter to stimulate its expression and to promote DNA repair by homologous recombination (HR). Importantly, a clinically relevant PARP inhibitor reversed or prevented EMT in response to DNA damage while resensitizing tumor cells to other genotoxic agents. Overall, our observations shed light on the intricate relationship between EMT, DNA damage response, and PARP inhibitors, providing potential insights for in cancer therapeutics.

Mechanisms of microRNA Regulation of the Epithelial–Mesenchymal Transition (EMT) in Lung Cancer

Lung cancer remains the cancer with the highest mortality worldwide, largely due to a limited understanding of the precise molecular mechanisms that drive its progression. microRNAs (miRNAs) have emerged as crucial regulators of lung cancer progression by influencing key cellular processes, notably the epithelial–mesenchymal transition (EMT). EMT is a complex and potentially reversible process where epithelial cells lose their polarity and adhesion, reorganize their cytoskeleton, and transition to a mesenchymal phenotype, enhancing their migratory and invasive capacities. While EMT plays an essential role in normal physiological contexts such as tissue development and wound healing, it is also a critical mechanism underlying the progression and metastasis of lung cancer. This review aims to summarize the latest research findings on the role of endogenous and exosome-derived microRNAs in regulating EMT in lung cancer, focusing on studies conducted over the past five years. It also provides an overview of EMT’s essential molecular mechanisms to better understand how miRNAs regulate EMT in lung cancer.

The Role of lncRNA FEZF1-AS1 in Colorectal Cancer Progression Via the P53 Signaling Pathway.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators in the development of colorectal cancer (CRC). Previous studies indicate that lncRNA FEZF1-AS1 is highly expressed in CRC, but its role in modulating CRC via the P53 signaling pathway remains unclear. In this study, we found that FEZF1-AS1 promotes the growth of the CRC cell line (HCT116) and drives epithelial-mesenchymal transition (EMT) through the P53 signaling pathway. Our data showed that FEZF1-AS1 expression is significantly upregulated in HCT116, and elevated levels of FEZF1-AS1 are associated with poor prognosis in patients with CRC. In addition, the knockdown of FEZF1-AS1 markedly inhibited the proliferation of HCT116 by inducing cell cycle arrest. Knockdown of FEZF1-AS1 depletion also led to apoptosis in CRC cells by suppressing the P53 signaling pathway and EMT, thereby reducing their viability, proliferation, migration, and invasion. In summary, this study confirmed that FEZF1-AS1 regulates the growth of junction HCT116 through P53 signaling pathway and inhibiting EMT, providing new insights for the potential therapeutic strategies against CRC.

Fluorescence-guided tumor visualization of colorectal cancer using tumor-initiating probe yellow in preclinical models

Fluorescence-guided surgery has emerged as an innovative technique with promising applications in the treatment of various tumors, including colon cancer. Tumor-initiating probe yellow (TiY) has been discovered for identifying tumorigenic cells by unbiased phenotypic screening with thousands of diversity-oriented fluorescence library (DOFL) compounds in a patient-derived lung cancer cell model. This study demonstrated the clinical feasibility of TiY for tumor-specific fluorescence imaging in the tissues of patients with colorectal cancer (CRC). To evaluate the efficacy of TiY in tumor imaging, surgical specimens were obtained, consisting of 36 tissues from 18 patients with CRC, for ex vivo molecular fluorescence imaging, histology, and immunohistochemistry. Orthotopic and chemically induced CRC mice models were administered TiY topically, and distinct tumor lesions were observed in 10 min by real-time fluorescence colonoscopy and ex vivo imaging. In a hepatic metastasis mouse model using splenic injection, TiY accumulation was detected in metastatic liver lesions through fluorescence imaging. Correlation analysis between TiY intensity and protein expression, assessed via immunohistochemistry and Western blotting, revealed a positive correlation between TiY and vimentin and Zeb1, which are known as epithelial–mesenchymal transition (EMT) markers of cancers. A comparative analysis of TiY with other FDA-approved fluorescence probes such as ICG revealed greater quantitative differences in TiY fluorescence intensity between tumor and normal tissues than those observed with ICG. Altogether, these results demonstrated that TiY has a strong potential for visualizing CRC by fluorescence imaging in various preclinical models, which can be further translated for clinical use such as fluorescence-guided surgery. Furthermore, our data indicate that TiY is preferentially uptaken by cells with EMT induction and progression, and overexpressing vimentin and Zeb1 in patients with CRC.

A computational analysis of the oncogenic and anti-tumor immunity role of P4HA3 in human cancers

Prolyl-4-hydroxylase subunit alpha3 (P4HA3) is a triple helical procollagen synthesis protein. The role of P4HA3 in cancer development is not well known and lacks comprehensive analyses among human cancers. This study aimed to investigate the relationship between P4HA3 expression and anti-tumor immunity and its prognostic value in pan-cancer. P4HA3 expression was analyzed from TIMER2.0, GTEx, GEPIA2.0 and TCGA databases. Genetic and DNA methylation alterations, survival analysis and proteins co-expression analysis of P4HA3 in cBio Cancer Genomics Portal, TCGA, GSCA and TIMER2.0. The correlation between P4HA3 expression and immune infiltration was analyzed by TIDE, XCELL, MCPCOUNTER, and EPIC. We performed EdU and transwell experiments to evaluate the influence of P4HA3 on the proliferation, migration and invasion abilities of different tumors. Patients derived xenograft (PDX) and subcutaneous transplantation models were utilized to explore the correlation between P4HA3 and immunotherapy response in triple-negative breast cancer (TNBC). Among 33 types of cancers, P4HA3 had generally different expression between different tumors, further analysis showed that the expression of P4HA3 was correlated with the cells infiltration of the tumor microenvironment (TME). The expression of P4HA3 was positively with the cell proliferation markers and epithelial-mesenchymal transition (EMT) markers. Moreover, P4HA3 deficiency inhibited the proliferation, migration and invasion abilities of tumor cells, and promoted anti-tumor immunotherapy of PD-1/PD-L1 inhibitor. This pan-cancer analysis of P4HA3 provides a comprehensive understanding of its oncogenic and prognosis role in different cancers, P4HA3 abnormal expression could be a useful biomarker for predicting the effectiveness of immunotherapy in cancer patients.

Research Progress on Epicardial Repair After Myocardial Injury.

Myocardial Injuries, such as myocardial infarction, trigger complex biological responses. The epicardium, known for its regenerative capabilities, plays a pivotal role in cardiac repair by undergoing activation and subsequent cellular transformations. This review examines the mechanisms of epicardial activation after myocardial injury, focusing on epithelial-mesenchymal transition, cell proliferation, and cell migration. It underscores the significance of the epicardium in heart repair processes and discusses potential implications for developing novel cardiac therapies. These insights may pave the way for leveraging epicardial cell dynamics to enhance cardiac regeneration, ultimately reducing the morbidity associated with heart disease.

Epoxymicheliolide Reduces Radiation-Induced Senescence and Extracellular Matrix Formation by Disrupting NF-κB and TGF-β/SMAD Pathways in Lung Cancer.

Lung cancer is a major cause of cancer-related mortality, and radiotherapy is often limited by tumor resistance and side effects. This study explores whether epoxymicheliolide (ECL), a compound from feverfew, can enhance radiotherapy efficacy in lung cancer. We tested ECL on A549 and PC-9 lung cancer cell lines to evaluate its effect on x-ray irradiation. We measured apoptosis, NF-κB pathway inhibition, TGF-β secretion reduction, and epithelial-mesenchymal transition suppression. Invivo, C57BL/6 mice with lung tumors received ECL and radiotherapy. ECL enhanced the antiproliferative effects of x-ray irradiation, induced apoptosis in senescent cells, inhibited the NF-κB pathway, reduced TGF-β levels, and suppressed epithelial-mesenchymal transition. ECL also inhibited tumor growth and improved survival in mice. ECL is a promising adjunct to radiotherapy for lung cancer, improving treatment outcomes by targeting multiple tumor progression mechanisms. It offers potential for enhanced management of lung cancer.

KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation.

Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.

NSUN2 Promotes Head and Neck Squamous Cell Carcinoma Progression by Targeting EMT-Related Gene LAMC2 in an m5C-YBX1-Dependent Manner

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is a prevalent and aggressive cancer with high rates of metastasis and poor prognosis. Recent research highlights the role of 5-methylcytosine (m5C) in cancer progression. NSUN2, an m5C methyltransferase, has been implicated in various cancers, but its role in HNSCC remains elusive. Methods: NSUN2 expression and its impact on HNSCC were analyzed by using clinical samples and bioinformatic analysis. m5C-Bis-Seq was used to assess changes in mRNA m5C modification and identify downstream targets. Both in vitro and vivo studies were performed to evaluate the impact of NSUN2 manipulation on tumor growth and metastasis. Results: Results indicated that NSUN2 was significantly upregulated in HNSCC tissues compared to normal tissues and was associated with poor prognosis. NSUN2 knockdown led to decreased cell proliferation, migration, and invasion in vitro and reduced tumorigenicity and lymph node metastasis in vivo. m5C-Bis-Seq revealed altered m5C-modification patterns upon NSUN2 knockdown, with LAMC2 identified as a key downstream target. Conclusions: NSUN2-mediated m5C-modification enhanced LAMC2 stability, promoting epithelial–mesenchymal transition (EMT) signaling pathways. These findings demonstrate that NSUN2 promotes the initiation and progression of HNSCC by stabilizing the LAMC2 transcript through m5C-dependent mechanisms, offering a promising epitranscriptomic-targeted therapeutic approach for HNSCC.

Knockdown of Inhibin Beta A Reversed the Epithelial Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance and Enhanced the Therapeutic Effect of Radiotherapy in Non-Small Cell Lung Cancer.

Lung cancer is a malignant tumor with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately half of all lung cancer cases. Inhibin beta A (INHBA) is a ligand of the transforming growth factor-beta superfamily. This study aimed to analyze the function of INHBA in NSCLC resistance cells. Gene Expression Omnibus and The Cancer Genome Atlas databases were used to identify differentially expressed genes (DEGs) in NSCLC resistance cells and patients. DEGs were further analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. A colony formation assay was performed to determine cell growth. Cell migration and invasion were tested by Transwell assay. Epithelial-mesenchymal transition (EMT)-related genes were analyzed using qRT-PCR and Western blot analysis. Using bioinformatics tools, INHBA was demonstrated to be overexpressed in NSCLC resistant cells and patients. Gefitinib treatment affected NSCLC resistant cells. Additionally, INHBA silencing or X-ray treatment suppressed the growth and metastasis of NSCLC resistant cells. Moreover, the combined application of INHBA silencing and X-ray treatment enhances the therapeutic effects. Moreover, EMT has been confirmed to occur in NSCLC resistant cell lines. Both INHBA silencing and X-ray treatment inhibited EMT development. This study demonstrated that INHBA silencing ameliorates EGFR-TKI resistance and enhances the therapeutic effect of radiotherapy in NSCLC.