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Gliomas, the most prevalent primary malignancy of the central nervous system, is characterised by its high mortality rates and unfavourable prognosis. Despite extensive research, the underlying mechanisms of glioma pathogenesis remain elusive. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases provided the lower-grade gliomas (LGG) transcriptome and related clinical data, which were downloaded separately. It was determined what the clinical data differences were between the two groups based on the median reticulon-4 (RTN4) expression group. The R language's survminer tool was utilised to examine the variations in survival between the RTN4 high and low-expression groups. The GeneMANIA database was searched for genes that might interact with RTN4, and these genes were then used to create extensive coexpression networks. Cox regression analysis, both univariate and multivariate, was used to filter out the independent prognostic factors influencing tumour growth. Based on independent prognostic parameters, a nomogram was created to predict prognosis. The model was assessed both internally and externally using receiver operating characteristic curve (ROC) and correcting curves. The R cibersort package was utilised to assess the level of immune infiltration abundance. We further validated our findings with clinical tissues using immunohistochemistry approaches. Statistical significance was determined using the Wilcoxon signed-rank test, with a p value of < 0.05 considered significant. RTN4 expression in the tumour group was higher than in the normal group (p < 0.001), and a high-expression level was linked to a poor prognosis (p = 0.028). Patients with elevated RTN4 expression exhibited significant differences from normal brain tissue samples when stratified analysis of LGG patients by sex or radiation treatment was performed (p < 0.001). The immune cell infiltration data demonstrated that the two groups' expressions of various immune cells differed, with pDC cells showing the greatest correlation (-0.421). Univariate and multivariate Cox regression study showed that RTN4, isocitrate dehydrogenase (IDH) mutation, 1p19q codeletion and nia age could be employed as independent prognostic factors for LGG, and the correction curve of the model fit well. Ultimately, clinical samples' immunohistochemistry revealed that RTN4 was markedly overexpressed in low-grade gliomas. High RTN4 expression was strongly associated with a poor prognosis in LGG patients. RTN4 may serve as a prognostic biomarker for patients with LGG and represents a potential therapeutic target for immunotherapy in this patient population., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: Radioresistance-induced locoregional recurrence remains a major cause of low survival rates. However, the mechanism of treatment failure in these lung cancer patients has not been determined. In the current study, we tried to explore the potential molecular mechanism., Methods: The fractionated irradiations were continued until the total concentration reached 80 Gy, and we established radioresistant subclones derived from A549 lines (designated as A549/R). The MTT assay, wound healing assay, transwell assay, and soft agar colony formation assay were employed to detect the proliferation, migration, invasion, and clonogenicity of the cells, respectively. Western blot and Fluorescence Activating Cell Sorter (FACS) indicated the expression of the markers., Results: A549/R cells proliferated more slowly than the parental A549 cells. A significant acceleration in cell migration and invasion was revealed in A549/R cells compared with A549 cells. The expression levels of mesenchymal markers (N-cadherin, vimentin, claudin-1, and Snail) increased, while epithelial markers (E-cadherin and β-catenin) decreased in A549/R cells. Meanwhile, the expression levels of stemness markers (Oct4, Notch1, and CD133) increased in A549/R cells, and A549/R cells showed more sphere-forming activity compared with A549 cells., Conclusion: Fractionated irradiation could promote epithelial-mesenchymal transition and enhance the migration, invasion, and stemness-like properties in A549 cells, elucidating the possible radioresistance mechanisms of the cancer cells., (© 2021 by the Association of Clinical Scientists, Inc.)

Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.

As a potential drug/gene delivery system, the ultrasound-targeted microbubble destruction (UTMD) system can be used as a vehicle as well as increasing the permeability of biological barriers to enhance the effect of tumor treatment. However, the effect of UTMD in the tumor EMT process is unknown. In this study, we aimed to investigate the potential and mechanism of UTMD induced oxidative stress in inhibiting EMT of breast cancer. Human breast MDA231 cells were treated with microbubble (MB), ultrasound (US) and UTMD, respectively. The generation of oxidative stress, the levels of miR-200c, ZEB1 and vimentin, and the numbers of migratory cells were evaluated quantitatively and qualitatively by the measurement of intracellular reactive oxygen species (ROS), qRT-PCR, western blot assay, and transwell assay. Then, to evaluate the role of UTMD-induced oxidative stress and miR-200c in the epithelial-mesenchymal transition (EMT) inhibition, the ROS scavenger N-acetyl-L-cysteine (NAC) and miR-200c inhibitor were used before UTMD treatment. We found that UTMD induced oxidative stress, upregulated the expression of miR-200c, downregulated the expression of ZEB1 and vimentin and suppressed the MDA231 cell migration. The addition of NAC and miR-200c inhibitor had an opposite impact on the expression of miR-200c and ZEB1, thus hindered the effects of UTMD on MDA231 cells EMT. In conclusion, UTMD can inhibit the EMT characteristics of MDA231 cells. The mechanism may be related to the regulation of the miR-200c/ZEB1 axis through the generation of ROS induced by UTMD, which may provide a new strategy to prevent the tumor cells EMT under UTMD treatment.

Pancreatic ductal adenocarcinoma (PDAC) tumours exhibit a high level of heterogeneity which is associated with hypoxia and strong resistance to chemotherapy. The RNA splicing protein polypyrimidine tract-binding protein 3 (PTBP3) regulates hypoxic gene expression by selectively binding to hypoxia-regulated transcripts. We have investigated the role of PTBP3 in tumour development and chemotherapeutic resistance in human PDAC tissues and pancreatic cancer cells. In addition, we determined the sensitivity of cancer cells to gemcitabine with differential levels of PTBP3 and whether autophagy and hypoxia affect gemcitabine resistance in vitro. PTBP3 expression was higher in human pancreatic cancer than in paired adjacent tissues. PTBP3 overexpression promoted PDAC proliferation in vitro and tumour growth in vivo, whereas PTBP3 depletion had opposing effects. Hypoxia significantly increased the expression of PTBP3 in pancreatic cancer cells in vitro. Under hypoxic conditions, cells were more resistance to gemcitabine. Knockdown of PTBP3 results in decreased resistance to gemcitabine, which was attributed to attenuated autophagy. We propose that PTBP3 binds to multiple sites in the 3'-UTR of ATG12 resulting in overexpression. PTBP3 increases cancer cell proliferation and autophagic flux in response to hypoxic stress, which contributes to gemcitabine resistance., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies without effective screening strategy during the early stage. Therefore, a novel screening panel was identified based on potential biomarkers associated with PDAC using the gene expression profile. The dataset GSE15471, which was downloaded from the Gene Expression Omnibus (GEO) database, included matching pairs of normal and tumor tissue samples from the resected pancreas of 39 pancreatic cancer patients. We used the online tool GEO2R to screen and pick out the differentially expressed genes (DEGs). Then we performed functional and pathway enrichment and constructed a DEG-associated protein-protein interaction (PPI) network by searching interacting genes in STRING. By using the visualization software Cytoscape, we sorted the modules in the PPI network and hub genes of DEGs through the MCODE and CytoHubba plugins. In total, 326 DEGs, including 306 upregulated genes and 20 downregulated genes, were targeted in PDAC. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway and gene ontology (GO), based on the Database for Annotation, Visualization, and Integrated Discovery (DAVID), revealed that the DEGs are mainly involved in 'PI3K-Akt signaling pathway,' 'Focal adhesion,' and 'ECM-receptor interaction.' In addition, top 50 core genes were identified from the PPI network by CytoHubba. Gene Expression Profiling Interactive Analysis (GEPIA) survival analysis showed that high expressions of KRT7, KRT19, SEMA3C, ITGA2, MYOF, and ANXA1 may predict poor survival outcome in PDAC. Finally, Oncomine confirmed that the high expressions of these genes were strongly related to cancer grade. These hub genes and regulators straightened out the molecular pathways and recurrence mechanisms in PDAC and could be used as targets for PDAC's diagnosis, treatment, and prognostic prediction.

Background: Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC., Methods: LOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting., Results: LOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis., Conclusions: Taken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC.

Background: Glioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment., Methods: Data from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells., Results: By bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer., Conclusions: ETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients.

Yes-associated protein (YAP) is a major downstream molecular of the Hippo pathway, which plays important role in cancer development. Netrin-1 conveys oncogenic activity in many types of malignant tumors. However, the downstream signaling of netrin-1 mediating its oncogenic effects in gastric cancer (GC) is not well defined. Here, we aim to investigate the role of netrin-1 in metastasis potential of GC by regulating YAP. In this study, we showed that netrin-1 inhibition significantly decreased migration and invasion abilities of GC cells, while netrin-1 overexpression effectively reversed this effect. We also demonstrated that netrin-1 upregulated YAP expression via its transmembrane receptor neogenin. Furthermore, our in vitro and in vivo results showed that the effect of netrin-1 on GC cells migration and invasion abilities was regulated by YAP. Collectively, our results defined netrin-1 as a positive regulator of malignant tumor metastasis in GC by activating the YAP signaling, with potential implications for new approaches to GC therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aims: Phosphoserine aminotransferase 1 (PSAT1) is over-expressed in many carcinoma tissues, however little is known regarding its expression and function in esophageal carcinogenesis. This study investigated the expression of PSAT1 in human esophageal squamous cell carcinoma (ESCC) tissues to determine the relationship between PSAT1 expression and clinicopathological factors., Methods: The expression of PSAT1 in 64 surgical resections from esophageal carcinogenesis patients was examined by quantitative RT-PCR and immunohistochemistry and the results were compared with clinicopathological factors. In vitro experiments were performed in ESCC cells overexpressing PSAT1 to measure cell viability and invasion. Tumor formation in vivowas examined by injection of tumor cells into immunocompromised mice subcutaneously., Results: PSAT1 expression was elevated in ESCC tissues compared to normal esophageal tissues. Increased PSAT1 expression was significantly associated with stage of disease, lymph node metastasis, distant metastasis and poor prognosis. In vitro, PSAT1 overexpression promoted ESCC cell proliferation and matrigel invasion. In vivo, injection of mice with ECSS cells overexpressing PSAT1 enhanced tumor formation. Western blot analysis revealed that PSAT1 upregulated the expression and/or activity of GSK3β/Snail., Conclusion: PSAT1 plays a crucial role in the development of ESCC and predicts poor survival. Therefore, PSAT1 may be a promising novel anticancer therapeutic target., (© 2016 S. Karger AG, Basel.)

Esophageal squamous-cell carcinoma (ESCC) is one of the most common tumors worldwide. Recent studies suggested that long noncoding RNAs (lncRNAs) might play a key role in regulating cellular processes and cancer progression. One of the lncRNAs, urothelial carcinoma associated 1 (UCA1), is known to be dysregulated in several cancers, including bladder carcinoma, colorectal, melanoma, breast, gastric, and ESCC. However, contributions of UCA1 to ESCC remain largely undiscovered. In order to understand the role and mechanisms underlying UCA1 in ESCC, the association of UCA1 expression with risk of esophageal cancer development was determined in 106 esophageal cancer tissues of ESCC patients and adjacent normal tissues using real-time reverse-transcription polymerase chain reaction (PCR). The relative expression of UCA1 was significantly reduced in cancer versus adjacent normal tissues suggesting an enhanced risk of esophageal cancer. To investigate the biological functions of UCA1 in ESCC, it was of interest to examine whether overexpression of UCA1 might influence cell proliferation, apoptosis, cell cycle distribution, migration, and invasion in vitro using EC109 cells. Our results demonstrated that UCA1 decreased cell proliferation, migration, invasion, and cell cycle progression of EC109 cells. Further, mRNA microarray analysis of overexpressed UCA1 in EC109 cells revealed that abnormal expression of UCA1 also inhibited the Wnt signaling pathway. Gene levels of DKK1 were elevated while C-myc fell significantly in overexpressed UCA1 EC109 cells. Interestingly, Western blot demonstrated no significant differences in relative expression of CTNNB1 (β-catenin) but marked reduction in β-catenin (active form) levels in both total and nuclear proteins. These results suggest that UCA1 may inhibit ESCC growth by regulating the Wnt signaling pathway. In conclusion, UCA1 may be a novel biomarker involved in ESCC development that may provide a potential therapeutic target for ESCC.

Objectives: To study the effects of the miR-324-5p on the glioma cells proliferation via the targeted regulation of the glioma-associated oncogene 1., Methods: The luciferase reporter gene was used to test whether the glioma-associated oncogene 1 was the target of the miR-324-5p microRNA. The glioma-associated oncogene 1 expression was detected by Western blot. The proliferation and cell cycle were evaluated by MTT assay and flow cytometry., Results: The glioma-associated oncogene 1 is a target of the miR-324-5p. An over-expressed miR-324-5p could reduce the cell survival rate and increase the G1/G0 phase rate in the glioma cell lines., Conclusions: The miR-324-5p can inhibit proliferation of the glioma cells via the targeted regulation of the glioma-associated oncogene 1.

Background: Among the different types of breast cancer, basal-like breast cancer (BLBC) has an extremely poor prognosis due to its high rate of recurrence and metastasis. The present study aimed to investigate the correlation between the expression of Slug, E-cadherin, and vimentin, and the clinicopathological characteristics and prognosis of patients with BLBC. We further inferred from these findings whether Slug leads to a poor prognosis in patients with BLBC through epithelial-mesenchymal transition (EMT)., Methods: Immunohistochemistry was performed for 441 patients with breast cancer to determine the expression levels of Slug, E-cadherin, and vimentin. The correlation between protein expression and clinicopathological characteristics of patients with BLBC was evaluated, and these patients were followed up to determine survival rate., Results: High Slug and low E-cadherin expression in BLBC patients closely correlated with histological grade, lymph node metastasis, tumor-node-metastasis (TNM) stage, and lymphatic vessel metastasis. Survival analysis revealed that the poor prognosis of BLBC is associated with TNM stage, high Slug and vimentin expression, and low E-cadherin levels., Conclusions: High Slug expression is closely correlated with poor prognosis in patients with BLBC. We speculate that this may be attributed to the involvement of Slug in the EMT of BLBC., (Copyright © 2012 Wiley Periodicals, Inc.)