Development Of Multiple Tumors Research Articles

Role of molecular genetic factors in formation of the clinical type of neurofibromatosis type 2

Neurofibromatosis type 2 is a hereditary disease with predisposition to the development of multiple tumors of the central and peripheral nervous system. The disease is characterized by significant variability in the clinical picture; the number of neoplasms, their location and growth rate largely determine the severity of the course. However, assessing the rate of tumor growth requires the availability of a consistent series of instrumental studies conducted within a certain time range, which is not always available at the time of initial treatment. In this study, based on quantitative (age of onset, age of examination) and qualitative (large number of intracranial tumors, large number of spinal tumors, severity of neurological symptoms, mosaic status of the genetic variant) characteristics, an alternative classification of clinical subtypes of neurofibromatosis type 2 was developed. We have revealed statistically significant differences (p-value = 0.037) in the representation of Halliday prognostic classes between the groups identified using the proposed classification which allows us to suggest the possibility of integrating this approach into clinical practice.

Role of molecular genetic factors in formation of the clinical type of neurofibromatosis type 2

Neurofibromatosis type 2 is a hereditary disease with predisposition to the development of multiple tumors of the central and peripheral nervous system. The disease is characterized by significant variability in the clinical picture; the number of neoplasms, their location and growth rate largely determine the severity of the course. However, assessing the rate of tumor growth requires the availability of a consistent series of instrumental studies conducted within a certain time range, which is not always available at the time of initial treatment. In this study, based on quantitative (age of onset, age of examination) and qualitative (large number of intracranial tumors, large number of spinal tumors, severity of neurological symptoms, mosaic status of the genetic variant) characteristics, an alternative classification of clinical subtypes of neurofibromatosis type 2 was developed. We have revealed statistically significant differences (p-value = 0.037) in the representation of Halliday prognostic classes between the groups identified using the proposed classification which allows us to suggest the possibility of integrating this approach into clinical practice.

Comparison of Socio-demographic Characteristics, Tumour Features, and Surgical Treatment Outcomes in Phenotypic Variants of Basal Cell Carcinoma

Abstract Background: Basal cell carcinoma (BCC) cases exhibit variations in tumour number, location, and growth patterns. While some patients develop only one BCC, approximately one-third of patients later develop one or more additional lesions. Aims: The aim of the study was to identify risk factors for further BCC lesions in patients with different phenotypic presentations. Materials and Methods: We retrospectively evaluated 1052 histopathologically diagnosed tumours of 861 patients, who were divided into four phenotypic presentation groups according to tumour number at initial diagnosis and during follow-up. Age, sex, tumour characteristics, surgical margins, re-excision and residual tumour rates were compared. Univariate and multivariate logistic regression analyses were performed to determine risk factors for multiple tumour development. Results: There were 723 patients in the single presentation phenotype 1 (SPP1) group, 19 in the SPP-more group, 114 in the multiple presentation phenotype (MPP)-cluster initial group, and five patients in the MPP-cluster later group. Male sex was more common in the MPP-cluster later group (P = 0.028). The mean age was lower in the SPP1 and SPP-more groups (P = 0.002). Ear involvement was more common in the MPP-cluster later group (P < 0.05). Superficial and basosquamous subtypes were more common in the SPP-more and MPP-cluster later groups (P < 0.05). Re-excision and residual tumour rates were lowest in the SPP1 group (P < 0.05). Age over 69 years, male sex, and periorbital or upper extremity location were significant risk factors for multiple tumour development (P < 0.05). Limitations: The limitations of our study include the inability to evaluate environmental risk factors, phenotypic and ethnic characteristics, and the short follow-up period for newly added patients. Conclusions: Predicting different phenotypic presentations by taking the age, gender, and tumour characteristics (localization, histopathological subtype) of the patients into account may allow new tumours to be detected at an early stage.

Neurofibromatoses: pathomorphological and clinical polymorphism, efficacy of targeted therapy

Neurofibromatoses are a group of inherited monogenic diseases with variable expression, characterized by the development of multiple tumors in tissues of neuroectodermal origin. Despite the similarity of phenotypic manifestations, each form differs in the spectrum of clinical manifestations, onset age of the first symptoms, severity of course, and approaches to treatment, the results of which are reflected in the prognosis and patients’ quality of life. The article analyzes the data from domestic and foreign studies on various forms of neurofibromatosis. The diagnostic criteria, pathogenesis, molecular considerations, and clinical manifestations, as well as treatment, including the example of 2 own clinical observations are discussed in this article.

Cuproptosis-related ceRNA axis triggers cell proliferation and cell cycle through CBX2 in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) has high morbidity and mortality. Despite substantial advances in treatment, the prognosis of patients with LUAD remains unfavorable. The ceRNA axis has been reported to play an important role in the pathogenesis of LUAD. In addition, cuproptosis is considered an important factor in tumorigenesis. The expression of CBX2 has been associated with the development of multiple tumors, including LUAD. However, the precise molecular mechanisms through which the cuproptosis-related ceRNA network regulates CBX2 remain unclear.MethodsThe DEGs between tumor and normal samples of LUAD were identified in TCGA database. The “ConsensusClusterPlus” R package was used to perform consensus clustering based on the mRNA expression matrix and cuproptosis-related gene expression profile. Then, LASSO-COX regression analysis was performed to identify potential prognostic biomarkers associated with cuproptosis, and the ceRNA network was constructed. Finally, the mechanisms of ceRNA in LUAD was studied by cell experiments.ResultsIn this study, the AC144450.1/miR-424-5p axis was found to promote the progression of LUAD by acting on CBX2. The expression of AC144450.1 and miR-424-5p can be altered to regulate CBX2 and is correlated with cell proliferation and cell cycle of LUAD. Mechanistically, AC144450.1 affects the expression of CBX2 by acting as the ceRNA of miR-424-5p. In addition, a cuproptosis-related model were constructed in this study to predict the prognosis of LUAD.ConclusionsThis study is the first to demonstrate that the AC144450.1/miR-424-5p/CBX2 axis is involved in LUAD progression and may serve as a novel target for its diagnosis and treatment.

Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non-canonical WNT pathway (FYN/STAT3).

A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the mechanism by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity. Using the Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, we bioinformatically analyzed YY1 expression in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells via epithelial-mesenchymal transition induction and neuroendocrine differentiation. Androgen deprivation therapy induced a decrease in YY1 protein ubiquitination, enhanced its stability, and thus enhanced the transcriptional activity of FZD8. Castration enhanced FZD8 binding to Wnt9A and mediated cellular plasticity by activating the non-canonical Wnt (FZD8/FYN/STAT3) pathway. We identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We believe that an in-depth investigation of the mechanism underlying YY1-mediated disease may lead to improved NEPC therapies.

Construction of a fluorescence sensing platform based on RISC and CRISPR/Cas12a for the assay of Ago2 enzyme activity

PurposeArgonaute 2 (Ago2) is a protein with nucleic acid endonuclease activity and is ubiquitous in eukaryotic cells. Ago2 is a core member of RNA interference and is involved in important gene regulation in the body and the development of multiple tumors by affecting oncogenic or oncogenic gene expression. Ago2 is a potential tumor biomarker. Therefore, the assay of Ago2 activity can help monitor the disease progression and prognosis and contribute to the study of the mechanism of disease development. MethodsAgo2-based nucleic acid endonuclease activity cleaves the target hairpin nucleic acid chain and progressively stimulates the hybridization chain reaction (HCR) in the sensing strategy, causing signal amplification to form specific dsDNA, which then triggers the powerful non-selective single nucleic acid chain cleavage activity of the CRISPR/cas12a system and releases the fluorescence signal in the reporter probe. ResultsThe sensitive assay of Ago2 enzyme activity was achieved using the biofunctional properties of RNA-induced silencing complex (RISC) and CRISPR/Cas12a. Under the optimized conditions, the fluorescence signal intensity of the assay was positively correlated with the activity concentration of Ago2, with an excellent linear response range of 0.02–20 nM and a limit of detection (LOD) of 10 pM. When applied to the assay of Ago2 in cell lysates, the experimental recovery was 93.33%-107.08%, and the sensing platform was able to detect the Ago2 content in the presence of interference specifically. ConclusionTherefore, the fluorescence sensing platform successfully constructed in this paper is suitable for the assay of endogenous Ago2 activity in complex samples, and the assay method has the advantages of high specificity, sensitive detection, easy operation and low instrumentation requirements, which is expected to be applied to the actual sample assay in clinical settings. Meanwhile, it provides an assay direction for the biofunctional analysis of nucleases and a feasible direction for applying RISC and Crispr/Cas12a in sensing analysis.

Isovalerylspiramycin I inhibits proliferation, migration and invasion of osteosarcoma cells by targeting Topoisomerase 1 and suppressing the ataxia telangiectasia and Rad3‐related/checkpoint kinase 1 pathway

AbstractPurposeTopoisomerase 1 (TOP1) plays a crucial role in various cell cycle processes and its dysregulation can lead to the development of multiple tumours. However, conventional TOP1 inhibitors such as topotecan and irinotecan have poor clinical efficacy in osteosarcoma (OS) patients. This is partly due to the activation of the ataxia telangiectasia and Rad3‐related/checkpoint kinase 1 (ATR/CHEK1) DNA damage repair pathway, which repairs TOP1 poison‐induced DNA lesions, compromises the cytotoxicity of TOP1 inhibitors and contributes to drug resistance. Therefore, there is a need to develop more effective TOP1 inhibitors for OS.Experimental designIn this study, we evaluated the antitumor effects of isovalerylspiramycin I (ISP‐I), a novel macrolide antibiotic, using various assays including CCK‐8 proliferation assays, wound healing migration assays, Transwell invasion assays, apoptosis, cell cycle, DNA replication and damage analyses on OS cells. We also performed a surface plasmon resonance‐high‐performance liquid chromatography‐mass spectrometry assay to identify ISP‐I's direct target protein in OS. Molecular docking analysis, thermoshift assays, enzyme activity assays and reverse tests were used to confirm ISP‐1′s target. Finally, we tested the efficacy of ISP‐I in vivo using a tumour xenograft model.ResultsOur results showed that ISP‐I significantly suppressed the growth of OS cells both in vitro and in vivo. Furthermore, ISP‐I dose‐dependently inhibited cell migration and invasion, and induced apoptosis and cell cycle arrest in OS cells. Mechanistically, ISP‐I directly bound to TOP1 and inhibited DNA replication. Additionally, ISP‐I significantly downregulated the ATR/CHEK1 pathway, which led to the suppression of DNA damage repair, ultimately augmenting DNA damage and triggering cell death.ConclusionsIn conclusion, our study suggests that ISP‐I could be a novel TOP1 inhibitor that does not activate the ATR/CHEK1 DNA damage repair pathway. This characteristic allows ISP‐I to synergistically inhibit OS cell proliferation, migration and invasion. ISP‐I may represent a promising candidate for the treatment of OS.

ELK3 Targeting AEG1 Promotes Migration and Invasion of Ovarian Cancer Cells under Hypoxia.

Ovarian cancer (OC) is one of the most common tumors in female reproductive organs with a five-year survival rate of less than 45%. Metastasis is a crucial contributor to OC development. ETS transcription factor (ELK3), as a transcriptional factor, have been involved in multiple tumor development. However, its role in OC remains elusive. In this study, we observed high expression of ELK3 and AEG1 in human OC tissues. OVCAR-3 and SKOV3 cells were treated with hypoxia to mimic tumor microenvironment in vivo. We found that the expression of ELK3 was significantly increased in cells under hypoxia compared with normoxia. ELK3 knockdown inhibited cell migration and invasion abilities under hypoxia. Moreover, ELK3 knockdown decreased β-catenin expression and inhibited the activation of Wnt/β-catenin pathway in SKOV3 cells under hypoxia. Astrocyte-elevated gene-1 (AEG1) has been reported to promote OC progression. Our results showed that the mRNA level of AEG1 was decreased when ELK3 knockdown under hypoxia. Dural luciferase assay confirmed that ELK3 bound to gene AEG1 promoter (-2005-+15) and enhanced its transcriptional activity under hypoxia. Overexpression of AEG1 increased the migration and invasion abilities of SKOV3 cell with ELK3 knockdown. In the absence of ELK3, the activation of β-catenin was recovered by AEG1 overexpression. To sum up, we conclude that ELK3 promotes AEG1 expression by binding to its promoter. ELK3 could promote migration and invasion of OC cells by targeting AEG1, which provides a potential basis for therapeutic approaches to OC.

Characteristic of molecular subtype based on lysosome-associated genes reveals clinical prognosis and immune infiltration of gastric cancer.

Lysosome are involved in nutrient sensing, cell signaling, cell death, immune responses and cell metabolism, which play an important role in the initiation and development of multiple tumors. However, the biological function of lysosome in gastric cancer (GC) has not been revealed. Here, we aim to screen lysosome-associated genes and established a corresponding prognostic risk signature for GC, then explore the role and underlying mechanisms. The lysosome-associated genes (LYAGs) were obtained from MSigDB database. Differentially expressed lysosome-associated genes (DE-LYAGs) of GC were acquired based on the TCGA database and GEO database. According to expression profiles of DE-LYAGs, we divided the GC patients into different subgroups and then explored tumor microenvironment (TME) landscape and immunotherapy response in LYAG subtypes using GSVA, ESTIMATE and ssGSEA algorithms. Univariate Cox regression analysis, LASSO algorithm and multivariate Cox regression analysis were adopted to identify the prognostic LYAGs and then establish a risk model for patients with GC. The Kaplan-Meier analysis, Cox regression analysis and ROC analysis were utilized to evaluate the performance of the prognostic risk model. Clinical GC specimens were also used to verify the bioinformatics results by qRT-PCR assay. Thirteen DE-LYAGs were obtained and utilized to distinguish three subtypes in GC samples. Expression profiles of the 13 DE-LYAGs predicted prognosis, tumor-related immunological abnormalities and pathway dysregulation in these three subtypes. Furthermore, we constructed a prognostic risk model for GC based on DEG in the three subtypes. The Kaplan-Meier analysis suggested that higher risk score related to short OS rate. The Cox regression analysis and ROC analysis indicated that risk model had independent and excellent ability in predicting prognosis of GC patients. Mechanistically, a remarkable difference was observed in immune cell infiltration, immunotherapy response, somatic mutation landscape and drug sensitivity. qRT-PCR results showed that compared with corresponding adjacent normal tissues, most screened genes showed significant abnormal expressions and the expression change trends were consistent with the bioinformatics results. We established a novel signature based on LYAGs which could be served as a prognostic biomarker for GC. Our study might provide new insights into individualized prognostication and precision treatment for GC.

Construction of an m6A-related lncRNA model for predicting prognosis and immunotherapy in patients with lung adenocarcinoma.

N6-methyladenosine (m6A)-related lncRNAs could be involved in the development of multiple tumors with an unknown role in lung adenocarcinoma (LUAD). Hence, gene expression data and clinical data of LUAD patients were acquired from The Cancer Genome Atlas Database. The prognostic m6A-related lncRNAs were identified through differential lncRNA expression analysis and Spearman's correlation analysis. The least absolute shrinkage and selection operator regression was used to establish the prognostic risk model, so as to evaluate and validate the predictive performance with survival analysis and receiver operating characteristic curve analysis. The expression of immune checkpoints, immune cell infiltration and drug sensitivity of patients in different risk groups were analyzed separately. A total of 19 prognostic m6A-related lncRNAs were identified to set up the prognostic risk model. The patients were divided into high- and low-risk groups based on the median value of the risk scores. Compared with the patients in the low-risk group, the prognosis of the patients in the high-risk group was relatively worse. The receiver operating characteristic curves indicated that this model had excellent sensitivity and specificity. Multivariate Cox regression analysis demonstrated that the risk score could be supposed as an independent prognostic risk factor. We highlighted that the risk scores were correlated with immune cell infiltration and drug sensitivity for constructing a prognostic risk model in LUAD patients based on m6A-related lncRNAs.

Comprehensive analysis of nicotinamide metabolism-related signature for predicting prognosis and immunotherapy response in breast cancer.

Breast cancer (BC) is the most common malignancy among women. Nicotinamide (NAM) metabolism regulates the development of multiple tumors. Herein, we sought to develop a NAM metabolism-related signature (NMRS) to make predictions of survival, tumor microenvironment (TME) and treatment efficacy in BC patients. Transcriptional profiles and clinical data from The Cancer Genome Atlas (TCGA) were analyzed. NAM metabolism-related genes (NMRGs) were retrieved from the Molecular Signatures Database. Consensus clustering was performed on the NMRGs and the differentially expressed genes between different clusters were identified. Univariate Cox, Lasso, and multivariate Cox regression analyses were sequentially conducted to develop the NAM metabolism-related signature (NMRS), which was then validated in the International Cancer Genome Consortium (ICGC) database and Gene Expression Omnibus (GEO) single-cell RNA-seq data. Further studies, such as gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, SubMap, and Immunophenoscore (IPS) algorithm, cancer-immunity cycle (CIC), tumor mutation burden (TMB), and drug sensitivity were performed to assess the TME and treatment response. We identified a 6-gene NMRS that was significantly associated with BC prognosis as an independent indicator. We performed risk stratification according to the NMRS and the low-risk group showed preferable clinical outcomes (P < 0.001). A comprehensive nomogram was developed and showed excellent predictive value for prognosis. GSEA demonstrated that the low-risk group was predominantly enriched in immune-associated pathways, whereas the high-risk group was enriched in cancer-related pathways. The ESTIMATE and CIBERSORT algorithms revealed that the low-risk group had a higher abundance of anti-tumor immunocyte infiltration (P < 0.05). Results of Submap, IPS, CIC, TMB, and external immunotherapy cohort (iMvigor210) analyses showed that the low-risk group were indicative of better immunotherapy response (P < 0.05). The novel signature offers a promising way to evaluate the prognosis and treatment efficacy in BC patients, which may facilitate clinical practice and management.

A pan-cancer analysis of the oncogenic role of polypyrimidine tract binding protein 1 (PTBP1) in human tumors

Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein that regulates several posttranscriptional events and is closely related to the development of multiple tumors. However, little is known about PTBP1. Thus, we carried out a systematic pan-cancer analysis to explore the relationship between PTBP1 and cancer. We used The Cancer Genome Atlas, Gene Expression Omnibus, and Human Protein Atlas datasets, as well as several bioinformatics tools, to explore the role of PTBP1 in 33 tumor types. The expression of PTBP1 in most tumor tissues was higher than that in normal tissues. Survival analysis indicated that overexpression of PTBP1 generally predicted poor overall survival in patients with tumors such as adrenocortical carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, and skin cutaneous melanoma. In addition, we compared the phosphorylation and immune infiltration of PTBP1 in cancer-associated fibroblasts between normal and primary tumor tissues and explored the putative functional mechanism of tumorigenesis mediated by PTBP1. These results provide clues to better understand PTBP1 from the perspective of bioinformatics and highlight its importance in various human cancers.

High yield of surveillance in patients diagnosed with constitutional mismatch repair deficiency

BackgroundConstitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessively inherited syndrome that is caused by biallelic pathogenic variants of the mismatch repair genes. It is characterised by the development...

Antisense oligonucleotides targeting exon 11 are able to partially rescue the NF2-related schwannomatosis phenotype in vitro

NF2-related schwannomatosis (NF2-related SWN) is an autosomal dominant condition caused by loss of function variants in the NF2 gene, which codes for the protein Merlin and is characterized by the development of multiple tumors of the nervous system. The clinical presentation of the disease is variable and related to the type of the inherited germline variant. Here, we tested if phosphorodiamidate morpholino oligomers (PMOs) could be used to correct the splice signaling caused by variants at±13 within the intron-exon boundary region and showed that the PMOs designed for these variants do not constitute a therapeutic approach. Furthermore, we evaluated the use of PMOs to decrease the severity of the effects of NF2 truncating variants with the aim of generating milder hypomorphic isoforms invitro through the induction of the in-frame deletion of the exon-carrying variant. We were able to specifically induce the skipping of exons 4, 8, and 11 maintaining the NF2 gene reading frame at cDNA level. Only the skipping of exon 11 produced a hypomorphic Merlin (Merlin-e11), which is able to partially rescue the observed phenotype in primary fibroblast cultures from NF2-related SWN patients, being encouraging for the treatment of patients harboring truncating variants located in exon 11.

MRGBP promotes colorectal cancer metastasis via DKK1/Wnt/β-catenin and NF-kB/p65 pathways mediated EMT

MRG domain binding protein (MRGBP) has been proposed to participate in the development of multiple tumors. However, the role of MRGBP in colorectal cancer (CRC) still remains largely unknown. Here, we found that MRGBP expression is significantly elevated in CRC, and that higher MRGBP expression correlates with poorer survival in CRC patients. Experiments in vivo and in vitro indicated that MRGBP promotes CRC cells proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) and xenograft tumor growth. Mechanically, for one thing, we discovered that MRGBP suppresses DKK1 expression, thus further activating the Wnt/β-catenin pathway in CRC cells. For another, MRGBP also enhances acetylation of NF-kB/p65 pathway. Treatment with Wnt/β-catenin and NF-kB pathways inhibitors further confirmed the mediation of these two pathways in MRGBP-promoted CRC cell processes. In conclusion, these findings together suggest that MRGBP promotes CRC progression via DKK1/Wnt/β-catenin and NF-kB/p65 pathways mediated EMT, identifying MRGBP as a promising prognostic and therapeutic target for CRC.

Diagnostic Strategies for Urologic Cancer Using Expression Analysis of Various Oncogenic Surveillance Molecules—From Non-Coding Small RNAs to Cancer-Specific Proteins

Urinary-tract-related tumors are prone to simultaneous or heterogeneous multiple tumor development within the primary organ. Urologic tumors have a very high risk of recurrence in the long and short term. This may be related to the disruption of homeostasis on the genetic level, such as the induction of genetic mutations due to exposure to various carcinogenic factors and the disruption of cancer suppressor gene functions. It is essential to detect the cancer progression signals caused by genetic abnormalities and find treatment therapies. In this review, we discuss the usefulness of tumor-expressing clinical biomarkers for predicting cancer progression. Furthermore, we discuss various factors associated with disturbed intracellular signals and those targeted by microRNAs, which are representative of non-coding small RNAs.

Identification and Assessment of Necroptosis-Related Genes in Clinical Prognosis and Immune Cells in Diffuse Large B-Cell Lymphoma.

BackgroundWith the unveiling of new mechanisms and the advent of new drugs, the prognosis of diffuse large B-cell lymphoma (DLBCL) becomes promising, but some patients still progress to the relapse or refractory stage. Necroptosis, as a relatively novel programmed cell death, is involved in the development of multiple tumors. There are no relevant studies on the prognostic significance of necroptosis in DLBCL to date.MethodsWe identified the differential necroptosis-related genes (NRGs) by comparing the DLBCL and normal control in GSE12195 and GSE56315 datasets. TCGA DLBC and GSE10846 containing clinical information and microarray expression profiling were merged as the entire cohort. We performed consensus clusters based on NRGs and two clusters were obtained. Kaplan–Meier (K-M) survival analysis, GSVA, GO, KEGG, and ssGSEA were used to analyze the survival, function, and immune microenvironment between two clusters. With LASSO and proportional hazard model construction, we identified differentially expressed genes (DEGs) between NRG clusters, calculated the risk score, established a prognostic model, and validated its value by calibration and ROC curves. The entire cohort was divided into the training and test cohort, and GSE87371 was included as an external validation cohort. K-M, copy number variation, tumor mutation burden, and drug sensitivity were also analyzed.ResultsWe found significant differences in prognosis between the two NRG clusters. Cluster A with a poor prognosis had a decreased expression of NRGs and a relatively suppressed immune microenvironment. GSVA analysis indicated that cluster A was related to the downregulation of the TGF-β signaling pathway and the activation of the Notch signaling pathway. The risk score had an accurate predictive ability. The nomogram could help predict the survival probability of DLBCL patients in the entire cohort and the external validation cohort. The area under the curve (AUC) of the nomogram, risk score, and International Prognostic Index was 0.723, 0.712, and 0.537, respectively. γ/δ T cells and Macrophage 1 cells decreased while Macrophage 2 cells and Natural Killer resting cells increased in the high-risk group. In addition, the high-risk group was more sensitive to the PI3K inhibitor and the PDK inhibitor.ConclusionWe explored the potential role of necroptosis in DLBCL from multiple perspectives and provided a prognostic nomogram for the survival prediction of DLBCL. Necroptosis was downregulated and was correlated with an immunosuppressed tumor microenvironment and poor prognosis in DLBCL. Our study may deepen the understanding and facilitate the development of new therapy targets for DLBCL.

LINC00173 promotes Wilms’ tumor progression through MGAT1-mediated MUC3A N-glycosylation

ABSTRACT Recent studies have unveiled that LINC00173 promotes small cell lung cancer progression. However, LINC00173 has not been studied in Wilms’ tumor (WT). N-glycosylation is a complex post-translational protein modification, and alterations of protein glycosylation have been identified to affect the development of multiple tumors, including WT. MGAT1, known as N-acetylglucosaminyltransferase I (GlcNAcT-1), could initiate synthesis of complex N-glycans, but it has never been related to LINC00173 in WT. This study aimed to explore if LINC00173 could impact WT progression via MGAT1. RT-qPCR and western blot were done to measure the expression and protein levels. Functional assays, as well as animal experiments were conducted to evaluate the function of genes in vivo and in vitro. Additionally, RNA pull-down, RIP, and dual-luciferase reporter assays were carried out to determine the molecular bindings. In vitro experiments proved that sh-LINC00173 inhibited WT cell invasion and promoted WT cell apoptosis, while in vivo experiments indicated sh-LINC00173 restrained WT progression. LINC00173 stabilized MGAT1 mRNA by recruiting HNRNPA2B1. Meanwhile, MGAT1 was verified to stabilize MUC3A protein by inducing N-glycosylation. In summary, our study first discovered that LINC00173 promoted WT progression through MGAT1-mediated MUC3A N-glycosylation, giving new clues to further understanding the mechanism underlying WT progression.

MFAP2 aggravates tumor progression through activating FOXM1/β-catenin-mediated glycolysis in ovarian cancer.

Ovarian cancer is one of the most common gynecological tumors that seriously endanger the health and quality of life of women. Microfibril-associated protein 2 (MFAP2) has been demonstrated to play crucial roles in the development of multiple tumors. However, the function of MFAP2 in ovarian cancer remains unclear. In this study, we found that MFAP2 was upregulated in ovarian cancer and cells and was positively correlated with FOXM1 and glycolysis-related genes. The results of Cell Count Kit-8, colony formation, and flow cytometry assays indicated that MFAP2 promoted cell proliferation. In addition, MFAP2 promotes cell proliferation, glucose uptake, lactate production; increases ATP levels, extracellular acidification ratio, and oxygen consumption ratio in ovarian cancer cells and increases the expression of glycolytic proteins. Further mechanistic analysis suggests that MFAP2 promotes FOXM1/β-catenin-mediated glycolysis signaling in ovarian cancer cells. Knockdown of MFAP2 inhibits ovarian cancer xenograft tumor growth and expression of Ki-67, MFAP2, FOXM1, GLUT1, HK2, and β-catenin in mice. In conclusion, MFAP2 promotes cell proliferation and glycolysis by modulating the FOXM1/β-catenin signaling pathway in ovarian cancer, which may offer a fresh insight into the treatment of ovarian cancer in the glycolysis pathway.