• ARAP1‐AS1
• DLBCL
• EMP1/PI3K/AKT
• apoptosis
• proliferation

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Lymphoma, Large B-Cell, Diffuse/pathology
• Lymphoma, Large B-Cell, Diffuse/genetics
• Lymphoma, Large B-Cell, Diffuse/metabolism
• Animals
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Phosphatidylinositol 3-Kinases/genetics
• Mice
• Signal Transduction
• RNA, Long Noncoding/genetics
• Gene Expression Regulation, Neoplastic
• Disease Progression
• Cell Proliferation
• Male
• Female
• Apoptosis
• Cell Line, Tumor
• Mice, Nude
• Xenograft Model Antitumor Assays

• EMP1
• RAS/RAF/MAPK
• diabetic cardiomyopathy
• oxidative stress
• pyroptosis

• Animals
• Pyroptosis/drug effects
• Rats
• Oxidative Stress/drug effects
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/drug effects
• Myocytes, Cardiac/pathology
• Glucose/metabolism
• MAP Kinase Signaling System/drug effects
• Gene Knockdown Techniques
• Cell Line
• ras Proteins/metabolism
• ras Proteins/genetics

• 2022J01677 Natural Science Fundation of Fujian Province

• cancer
• epithelial membrane protein 1
• metastasis
• prognosis
• tumor biomarkers

• Humans
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Neoplasms/metabolism
• Neoplasms/diagnosis
• Neoplasms/therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasm Proteins/metabolism
• Neoplasm Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Molecular Targeted Therapy/methods
• Receptors, Cell Surface

• CSTB2022NSCQ-JQX0032 Chongqing Science Fund for Distinguished Young Scholars
• CSTB2022BSXMJCX0005 Doctor Research Project of Chongqing

• Angiogenesis-related genes
• GEO
• Immune microenvironment
• Multiple myeloma
• Prognosis

• Humans
• Multiple Myeloma/genetics
• Multiple Myeloma/pathology
• Prognosis
• Neovascularization, Pathologic/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Biomarkers, Tumor/genetics
• Gene Regulatory Networks
• Databases, Genetic
• Gene Ontology
• Angiogenesis

• 2022LCZXKF-XY11, 2021LCZXXF-XY04, 2021LCZXXF-XY05, 2020LCZXKF-XY02 the Open Project of Yunnan Blood Clinical Medical Center
• 2023YGY2 the 920th Hospital of PLA Joint Logistics Support Force Science and Technology Program Youth Project
• 82360041 the National Natural Science Foundation of China
• NO. D-2018018 the Yunnan Health Training Project of High-level Talents
• No. 2018FE001 (-113) the Yunnan Applied Basic Research Projects-Joint Fund for Applied Basic Research of Kunming Medical University, the Yunnan Provincial Department of Science and Technology
• the Yunnan Applied Basic Research Projects–Joint Fund for Applied Basic Research of Kunming Medical University, the Yunnan Provincial Department of Science and Technology

Regulatory T cells (Tregs) and natural killer (NK) cells play an essential role in the development of bladder urothelial carcinoma (BUC).

To construct a prognosis-related model to judge the prognosis of patients with bladder cancer, meanwhile, predict the sensitivity of patients to chemotherapy and immunotherapy.

Bladder cancer information data was obtained from The Cancer Genome Atlas and GSE32894. The CIBERSORT was used to calculate the immune score of each sample. Weighted gene co-expression network analysis was used to find genes that will have the same or similar expression patterns. Subsequently, multivariate cox regression and lasso regression was used to further screen prognosis-related genes. The prrophetic package was used to predict phenotype from gene expression data, drug sensitivity of external cell line and predict clinical data.

The stage and risk scores are independent prognostic factors in patients with BUC. Mutations in FGFR3 lead to an increase in Tregs percolation and affect the prognosis of the tumor, and additionally, EMP1, TCHH and CNTNAP3B in the model are mainly positively correlated with the expression of immune checkpoints, while CMTM8, SORT1 and IQSEC1 are negatively correlated with immune checkpoints and the high-risk group had higher sensitivity to chemotherapy drugs.

Prognosis-related models of bladder tumor patients, based on Treg and NK cell percolation in tumor tissue. In addition to judging the prognosis of patients with bladder cancer, it can also predict the sensitivity of patients to chemotherapy and immunotherapy. At the same time, patients were divided into high and low risk groups based on this model, and differences in genetic mutations were found between the high and low risk groups.

• Natural killer cells
• Tregs
• Bladder cancer
• Weighted gene coexpression network analysis
• Bladder cancer treatment
• Immunotherapy
• Computational molecular biology

Peripheral myelin protein 22 (PMP22) and epithelial membrane proteins (EMP-1, -2, and -3) belong to a small hydrophobic membrane protein subfamily, with four transmembrane structures. PMP22 and EMPs are widely expressed in various tissues and play important roles in cell growth, differentiation, programmed cell death, and metastasis. PMP22 presents its highest expression in the peripheral nerve and participates in normal physiological and pathological processes of the peripheral nervous system. The progress of molecular genetics has shown that the genetic changes of the PMP22 gene, including duplication, deletion, and point mutation, are behind various hereditary peripheral neuropathies. EMPs have different expression patterns in diverse tissues and are closely related to the risk of malignant tumor progression. In this review, we focus on the four members in this protein family which are related to disease pathogenesis and discuss gene mutations and post-translational modification of them. Further research into the interactions between structural alterations and function of PMP22 and EMPs will help understand their normal physiological function and role in diseases and might contribute to developing novel therapeutic tools.

• Cancer
• Epithelial membrane protein
• Mutation
• Peripheral myelin protein 22
• Programmed cell death

Previous studies had shown that lncRNA HULC exhibited different effects in human cancers. However, the role of HULC was not reported in osteosarcoma. Hence, we designed this research to explore the function of HULC in osteosarcoma.

Firstly, HULC expression was measured in osteosarcoma tissues and cells via the RT-qPCR assay. The protein expression was detected through western blot. Then, CCK-8 and Transwell assays were conducted to measure cell proliferation, migration, and invasion.

The expression of HULC was obviously higher in osteosarcoma tissues and cells compared with normal control. Moreover, cell proliferation, migration, and invasion were inhibited by HULC knockdown in osteosarcoma cells. HULC overexpression markedly increased osteosarcoma cell proliferation and tumor size in vivo. Furthermore, HULC increased the activity of AKT-PI3K-mTOR pathway by blocking PTEN in osteosarcoma cells. LY294002 inhibited the phosphorylation of AKT, mTOR, and PI3K. Overexpressing HULC enhanced cell migration and invasion of SAOS-2 cells and MG63 cells, while LY294002 reversed the effects.

HULC enhanced the progression of osteosarcoma through targeting PTEN.

Epithelial membrane protein (EMP1), a member of the peripheral myelin protein (PMP22) family, is involved in the development of various human malignancies. However, the expression level of EMP1 and its functional role in head and neck squamous cell carcinoma (HNSCC) remain unclear to date. Ferroptosis, a newly characterized form of regulated cell death, plays an essential role in tumorigenesis. In this study, we aimed to investigate the expression levels of EMP1 in HNSCC and normal tissues, as well as to identify the function of EMP1 in regulating ferroptosis during the progression of HNSCC. To further explore the biological function of EMP1 in vitro, transient transfection was used to overexpress EMP1 in the HNSCC cell lines Hep2 and Detroit562. Functionally, our results indicated that EMP1 overexpression could not affect the initiation of ferroptosis directly but reinforced RSL3-induced ferroptosis on HNSCC cells. Furthermore, mechanical study indicated that EMP1 mediated the ferroptosis via cell density-regulated Hippo-TAZ pathway and regulated the expression of Rac1 and NOX1. In addition, our study demonstrated that EMP1 overexpression could promote gefitinib resistance by targeting the MAPK pathway. In summary, our findings indicate that EMP1 may act as an oncogene and serve as a therapeutic target against malignant progression of HNSCC.

ETS variant transcription factor 4 (ETV4) is a common cancer-promoting transcription factor and its expression has been found to be significantly upregulated in glioblastoma multiforme (GBM), as determined via analysis of the Gene Expression Profiling Interactive Analysis (GEPIA) database. In addition, our previous study demonstrated that ETV4 expression was highly positively correlated with epithelial membrane protein 1 (EMP1). The present study aimed to determine whether ETV4 could influence the activation of the PI3K/AKT/mTOR signaling pathway to affect the autophagy and apoptosis of GBM cells by regulating the transcriptional activity of EMP1. In addition to the analysis of the GEPIA database, the expression levels of ETV4 were also investigated in several different GBM cell lines. After interfering with the expression of ETV4, western blotting was used to detect the expression levels of autophagy- and apoptosis-related proteins, and a TUNEL assay was used to detect the levels of cell apoptosis. Dual luciferase reporter and chromatin immunoprecipitation assays were used to verify the potential binding site of ETV4 on EMP1. Western blotting was also used to analyze the expression levels of PI3K/AKT/mTOR signaling pathway-related proteins. The results of the current study revealed that the expression levels of ETV4 were significantly upregulated in GBM cell lines compared with those in normal glial cells. In the GBM cell line, LN-229, ETV4 was discovered to bind to the EMP1 promoter and positively regulate the expression of EMP1. The knockdown of ETV4 expression inhibited the PI3K/AKT/mTOR signaling pathway activity to promote autophagy and apoptosis, and this effect could be partially reversed by overexpressing EMP1. In conclusion, these findings indicated that the knockdown of ETV4 in GBM cells may reduce the transcriptional activation of EMP1 and thereby inhibit PI3K/AKT/mTOR signaling pathway activity to promote autophagy and apoptosis. This provides a novel insight into potential strategies for the treatment of GBM via the induction of autophagy-dependent apoptosis.

• ETS variant transcription factor 4
• autophagy-dependent apoptosis
• epithelial membrane protein 1
• glioblastoma multiforme
• mTOR

Intratumoral immune cells were reported to be associated with prognosis of bladder urothelial carcinoma (BUC). However, the role of immune cells related genes in BUC prognosis is less well defined. In the study, we analyzed data retrieved from the Cancer Genome Atlas database and found higher neutrophils and lower T cells infiltration in BUC tumor tissues were significantly correlated with patients’ worse prognosis. Additionally, the expression levels of 164 genes were significantly correlated with T cells and neutrophils proportions. A Cox proportional-hazards model integrating 6 genes expression (EMP1, RASGRP4, HSPA1L, AHNAK, SLC1A6, and PRSS8) was identified. The 6-gene signature outperformed other clinical factors in risk prediction and was an independent prognostic factor for BUC. The findings were further conformed in three Gene Expression Omnibus datasets (n=331) and Jiangsu Province Hospital cohort (n = 46). Gene set enrichment analysis revealed that the model was highly involved in some immune-related pathways. A comprehensive nomogram combining the model and other clinical parameters was finally constructed to facilitate clinical application. In conclusion, a T cell and neutrophil-associated 6-gene prognostic model was identified for the survival prediction of BUC patients.

• T cells
• bladder urothelial carcinoma
• neutrophils
• nomogram
• survival

• intercellular communication
• signal transduction
• stroma
• tumor invasion
• tumor microenvironment

• Apoptosis/physiology
• Cadherins/metabolism
• Cell Communication/physiology
• Cell Movement/physiology
• Cell Proliferation
• Coculture Techniques
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Proto-Oncogene Proteins c-akt/metabolism
• Receptors, Cell Surface/genetics
• Receptors, Cell Surface/metabolism
• Stromal Cells/physiology
• Tumor Microenvironment/physiology
• rac1 GTP-Binding Protein/metabolism

Ferroptosis is a regulated form of cell death characterized by iron dependency and increased lipid peroxidation. Initially assumed to be selectively induced in tumour cells, there is increasing evidence that ferroptosis plays an important role in pathophysiology and numerous cell types and tissues. Deregulated ferroptosis has been linked to human diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Along these lines, ferroptosis is a promising pathway to overcoming therapy resistance of cancer cells. It is therefore of utmost importance to understand the cellular signalling pathways and the molecular mechanisms underlying ferroptosis regulation, including context-specific effects mediated by the neighbouring cells through cell–cell contacts. Here, we give an overview on the molecular events and machinery linked to ferroptosis induction and commitment. We further summarize and discuss current knowledge about the role of cell–cell contacts, which differ in ferroptosis regulation between normal somatic cells and cancer cells. We present emerging concepts on the underlying mechanisms, address open questions, and discuss the possible impact of cell–cell contacts on exploiting ferroptosis in cancer therapy.

• cancer therapy
• cell–cell contacts
• epithelial–mesenchymal transition
• ferroptosis

MicroRNAs (miRNAs) are thought to be involved in the development of cisplatin (DDP) resistance in gastric cancer (GC). Using RNA sequencing analysis (RNA-seq), we found that miR-95-3p is associated with DDP resistance in GC. We discovered that miR-95-3p is highly expressed in DDP-resistant GC tissues and cell lines (SGC7901/DDP and AGS/DDP). Furthermore, results from the BrdU and MTT assays indicated that miR-95-3p promotes GC cell proliferation. Additionally, data from transwell chamber assay, wound healing test and in vivo experiments illustrated that miR-95-3p can effectively promote invasion, migration and tumorigenic capacity, respectively, of DDP-resistant GC cells. Subsequently, results from dual luciferase assay and qRT-PCR collectively indicated that EMP1 is a target of miR-95-3p with inhibitory function through suppression of the EMT process and drug-resistance proteins. Furthermore, PI3K/AKT was identified as a downstream pathway of miR-95-3p, which promotes DDP resistance in GC. In summary, miR-95-3p helped develop DDP-resistance through down-regulation of EMP1 and increasing phosphorylation of the PI3K/Akt pathway in GC.

• DDP resistance
• EMP1
• PI3K/AKT
• gastric cancer
• miR-95-3p

Glucocorticoid (GC), such as prednisolone, is an essential component of multidrug chemotherapy regimen for pediatric acute lymphoblastic leukemia (ALL). Resistance to GC in leukemia cells is associated with disease progression and poor prognosis. Despite the extensive use of GC for many years, molecular mechanisms underlying its resistance in ALL have not been fully uncovered. Recent studies have shown a potential role of EMP1, CASP1, and NLRP3 genes in prednisolone response. In this study on 148 pediatric B-ALL patients, we studied these three genes to assess their association with prednisolone response measured by day 8 blast count after 7 days of induction therapy with prednisolone. Intriguingly, ALL samples exhibited higher expression of EMP1 along with a low expression of CASP1 and NLRP3 compared to disease free normal bone marrow collected from patients with solid tumors. Among the three analyzed genes, only EMP1 was found to be overexpressed in prednisolone poor responders (p=0.015). Further, a comparison of gene expression between cytogenetic subtypes revealed higher expression of EMP1 in BCR-ABL subtype. Expression of EMP1 in multiple gene expression datasets was used for gene set enrichment analysis, which revealed TNF-α, IL-2-STAT5 signaling, inflammatory responses and hypoxia as the major positively associated pathways and E2F targets as negatively associated pathways. Interestingly, the clinical remission rate was higher in CASP1 high patients (p=0.048). In univariate survival analysis, higher EMP1 expression was associated with poor prognostic measures while higher expression of NLRP3 and CASP1 was associated with better prognostic measures in our data. Further, multivariate analysis revealed an independent association of high CASP1 and NLRP3 with a better prognosis. This study strengthens the available evidence that mRNA expression of EMP1, CASP1, and NLRP3 may serve as potential biomarkers for risk stratification of pediatric B-ALL patients.

• B-ALL
• CASP1
• EMP1
• NLRP3
• leukemia
• prednisolone resistance

• Glioblastoma
• Invasion
• PI3K/Akt pathway
• SAMMSON
• Viability

• Apoptosis/genetics
• Cell Line, Tumor
• Cell Survival/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinase/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Signal Transduction

• Prognostic markers
• Tumour biomarkers

• the National Nature Science Foundation of China (No. 31500935 to SC)

Glioblastoma (GBM) is an aggressive central nervous system (CNS) cancer and a serious threat to human health. The long noncoding RNA (lncRNA) HULC has been implicated in GBM, but the molecular mechanism is uncertain. This study used quantitative proteomic analysis for global identification of HULC-regulated proteins in glioblastoma cells and identification of potential biomarkers.

qRT-PCR was used to determine the expression of HULC in U87 cells stably transfected with HULC or an empty vector (control). The CCK-8 assay, transwell assay, and wound-scratch assay were used to measure cell proliferation, invasion, and migration. Quantitative proteomics using Tandem Mass Tag (TMT) labeling, high-performance liquid chromatography (HPLC) fractionation, and liquid chromatography–mass spectrometry (LC-MS/MS) analysis were used to identify differentially expressed proteins (DEPs). Screened proteins were validated by parallel reaction monitoring (PRM) and Western blotting.

Overexpression of HULC led to increased cell proliferation, invasion, and migration. HULC overexpression also led to significant upregulation of 37 proteins and downregulation of 78 proteins. Bioinformatics analysis indicated these proteins had roles in cellular component, biological process, and molecular function. PRM results of 8 of these proteins (PTK2, TNC, ITGAV, LASP1, MAPK14, ITGA1, GNA13, RRAS) were consistent with the LC-MS/MS and Western blotting results.

The results of present study suggest that lncRNA HULC promotes GBM cell proliferation, invasion, and migration by regulating RRAS expression, suggesting that RRAS may be a potential biomarker or therapeutic target for this cancer.

• LncRNA HULC
• PRM
• glioblastoma
• quantitative proteomics

Epithelial membrane protein 1 (EMP1), a member of the EMP family, is overexpressed in a large number of tumors and is thought to be a cellular connexin on the cell membrane and is involved in proliferation, invasion, metastasis of tumor cells, and epithelial-mesenchymal transition (EMT). Nevertheless, its biomedical function in ovarian cancer is still unclear.

EMP1 was detected in ovarian cancer cell lines by whole transcriptome resequencing. The mRNA of EMP1 was examined by qRT-PCR. The relationship between expression of EMP1 and clinical classification, metastasis, and shortened survival time in ovarian cancer specimens was analysed by immunohistochemical (IHC). The mechanism of EMP1 enhanced proliferation and invasion of ovarian cancer cells was determined by siRNA interference, colony formation, migration and invasion experiments, and Western blot.

EMP1 was up-regulated in ovarian cancer cell lines and ovarian cancer tissues in comparison with non-cancerous ovarian specimens. High expression of EMP1 in ovarian cancer specimens was obviously related to high clinical classification, metastasis, and shortened survival time. High expressed EMP1 facilitates cell proliferation, invasion and EMT in ovarian cancer cells. Over-expressed EMP1 increased the protein levels of RAS/RAF/MAPK/c-JUN.

Over-expressed EMP1 in ovarian cancer promotes tumor cell proliferation, invasion, and EMT by the MAPK signaling pathway.

• EMP1
• EMT
• MAPK
• ovarian cancer

The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

• glioma
• glutamate
• glutamate dehydrogenase
• glutaminase
• glutamine
• glutamine synthetase
• therapy

• apoptosis
• cancer progression
• cell migration
• cell proliferation
• transmembrane protein

• Grants-in-aid for Scientific Research Japan Society for the Promotion of Science
• Research Support Takeda Science Foundation