Association between tri-ponderal mass index and glucose metabolism disorder in children with obesity in China: A case-control study.

Obesity is a risk factor for glucose metabolism disorder. This study explored the association between the tri-ponderal mass index (TMI) and indicators of glucose metabolism disorder in children with obesity in China. This retrospective case-control study included children aged 3 to 18 years old diagnosed with obesity at Jiangxi Provincial Children's Hospital (China) between January 2020 and April 2022. Demographic and clinical characteristics were obtained from the medical records. Factors associated with glucose metabolism disorder were explored by logistic regression analysis. Pearson correlations were calculated to evaluate the relationships between TMI and indicators of glucose metabolism disorder. The analysis included 781 children. The prevalence of glucose metabolism disorder was 22.0% (172/781). The glucose metabolism disorder group had an older age (11.13 ±â€…2.19 vs 10.45 ±â€…2.33 years old, P = .001), comprised more females (76.8% vs 66.9%, P = .008), had a higher Tanner index (P = .001), and had a larger waist circumference (89.00 [82.00-95.00] vs 86.00 [79.00-93.75] cm, P = .025) than the non-glucose metabolism disorder group. There were no significant differences between the glucose metabolism disorder and non-glucose metabolism disorder groups in other clinical parameters, including body mass index (26.99 [24.71-30.58] vs 26.57 [24.55-29.41] kg/m2) and TMI (18.38 [17.11-19.88] vs 18.37 [17.11-19.88] kg/m3). Multivariable logistic regression did not identify any factors associated with glucose metabolism disorder. Furthermore, TMI was only very weakly or negligibly correlated with indicators related to glucose metabolism disorder. TMI may not be a useful indicator to screen for glucose metabolism disorder in children with obesity in China.

Serine/threonine-protein kinase D2-mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression.

Desmoglein-2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell-cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine-protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2-T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2-mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

The possibilities of LOXL4 as a prognostic marker for carcinomas.

Lysyl oxidase-like 4 (LOXL4), a member of lysyl oxidase family, is a copper and lysine tyrosylquinone-dependent amine oxidase that serves the role of catalyzing the cross-linking of elastin and collagen in the extracellular matrix. Numerous studies have shown a significant association between LOXL4 expression levels and tumor proliferation, migration, invasion and patients' prognosis and overall survival in different types of tumors. Here we review their relationship and the molecular pathogenesis behind them, aiming to explore the possibilities of LOXL4 as a prognostic marker for diverse carcinomas and provide some indications for further research in this field.

Secreted proteins encoded by super enhancer-driven genes could be promising biomarkers for early detection of esophageal squamous cell carcinoma.

BACKGROUND: Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). METHODS: We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy. RESULTS: Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907). CONCLUSIONS: Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.

A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer.

During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3ß signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target.

The Expression Pattern and Clinical Significance of Lysyl Oxidase Family in Gliomas.

LOX (Lysyl oxidase) family participates in the catalysis of collagen and elastin to maintain ECM homeostasis. Glioma is the most common primary brain tumor and LOX family has not been systemic studied in glioma. In this study, we found LOX family members are upregulated expressed in gliomas samples. A protein-protein interaction network (PPIN) was construct to visualize and understand the differential expression pattern, as well as functional annotation, for LOX family and their interacting proteins, which involved in collagen fibril organization and MAPK signaling pathway. Through subcellular localization distribution, the LOX family members distribute both intracellular and extracellular. All five LOX members are consistently significantly correlate with dendritic cell both in immune infiltrate of GBM and LGG. Survival analysis showed that high expression of LOX family is associated with a poor prognosis of gliomas patients. These analyses provide important clues to identify the potential biological roles for LOX family in gliomas, which might serve as diagnosis markers.

Construction and analysis of evaluation model for medical students' innovation competency based on research-oriented biochemistry and molecular biology course in China.

Presently, a variety of policies and measures has implemented to enhance the scientific research and innovation ability of medical students, but in the process of practice, there are many problems, such as they lack of independent topic selection ability, weak scientific research skills, lack of autonomous learning ability, the research results are simple and ineffective, limited teacher guidance time and so on. This paper attempted to build an effective model for the promotion of medical students' scientific research and innovation ability, in order to establish an efficacy evaluation model of the "Medical students' Innovative Scientific Research Program." Undergraduates, graduate assistants, and tutors were interviewed with the Behavioral Event Interview technique, and a questionnaire of efficacy evaluation characteristics concluded from the interviews was formed. The questionnaire was conducted on medical students in the Medical students' Innovative Scientific Research Program, and the constructed model was analyzed using reliability analysis, validity analysis, and variation analysis. At the same time, the experimental teaching models are summarized and combed, and compared with other methods such as independent sample test. The results show the model could effectively evaluate the efficacy of the Medical students' Innovative Scientific Research Program and its teaching model is effective in cultivating medical students' learning and scientific research ability. It can provide theoretical support and practical reference for the evaluation and reform of the teaching modes related to the cultivation of scientific and innovative ability of medical students.

Role of Integrin ß1 in the progression and chemo-resistance of esophageal squamous cell carcinoma.

Objective: Integrins have been shown to play an important role in the tumorigenesis of many cancers. In this work, we aimed to explore the expression and clinical value of Integrin α5ß1 in esophageal squamous cell carcinoma (ESCC), and the effect of integrin ß1 on the development and chemo-resistance of ESCC cells. Methods: The expression profiling of integrins was analyzed in the mRNA expression dataset of ESCC. The expression of Integrin α5ß1 in 278 cases of ESCC tissues and 62 cases of paracancerous tissues was detected by immunohistochemistry (IHC). The association between the expression of Integrin α5ß1 and the survival of ESCC patients was analyzed by Kaplan-Meier analysis. The effect of Integrin ß1 on the proliferation, migration, and invasion of ESCC cells was examined by MTS, Transwell migration, and Transwell invasion assay. The effect of Integrin ß1 and L1 cell adhesion molecule (L1CAM) on cisplatin resistance was detected by MTS and the signal pathways involved were analyzed by Western blotting. Results: Integrin ß1 and Integrin α5 were significantly up-regulated in ESCC. High expression of Integrin ß1 was also related to worse overall survival of ESCC patients and patients with low levels of both Integrin ß1 and Integrin α5 showed the shortest survival. Results of IHC revealed that Integrin α5ß1 was up-regulated in ESCC and its high expression was associated with poor prognosis and could serve as an independent prognostic factor. siRNA-mediated Integrin ß1 silencing or antibody blocking restrained the proliferation, migration, and invasion of ESCC cells. Simultaneous knockdown of Integrin ß1 and L1CAM reduced the cisplatin resistance of ESCC cells. Further studies showed that knockdown of Integrin ß1 and L1CAM suppressed the activity of Akt signaling with or without cisplatin treatment. Moreover, dual high expression of Integrin ß1 and L1CAM was related to worse overall survival of ESCC patients treated with preoperative chemotherapy. Conclusion: Integrin α5ß1 was up-regulated in ESCC and could be used as a new prognostic indicator for ESCC patients. In addition, Integrin ß1 was involved in the proliferation, invasion, and chemo-resistance of ESCC cells.

Construction of the Six-lncRNA Prognosis Signature as a Novel Biomarker in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignant gastrointestinal tumor threatening global human health. For patients diagnosed with ESCC, determining the prognosis is a huge challenge. Due to their important role in tumor progression, long non-coding RNAs (lncRNAs) may be putative molecular candidates in the survival prediction of ESCC patients. Here, we obtained three datasets of ESCC lncRNA expression profiles (GSE53624, GSE53622, and GSE53625) from the Gene Expression Omnibus (GEO) database. The method of statistics and machine learning including survival analysis and LASSO regression analysis were applied. We identified a six-lncRNA signature composed of AL445524.1, AC109439.2, LINC01273, AC015922.3, LINC00547, and PSPC1-AS2. Kaplan-Meier and Cox analyses were conducted, and the prognostic ability and predictive independence of the lncRNA signature were found in three ESCC datasets. In the entire set, time-dependent ROC curve analysis showed that the prediction accuracy of the lncRNA signature was remarkably greater than that of TNM stage. ROC and stratified analysis indicated that the combination of six-lncRNA signature with the TNM stage has the highest accuracy in subgrouping ESCC patients. Furthermore, experiments subsequently confirmed that one of the lncRNAs LINC01273 may play an oncogenic role in ESCC. This study suggested the six-lncRNA signature could be a valuable survival predictor for patients with ESCC and have potential to be an auxiliary biomarker of TNM stage to subdivide ESCC patients more accurately, which has important clinical significance.

Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation.

Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes the oxidative deamination ε-amino group of lysine. It is found that LOXL2 is a promotor for the metastasis and invasion of cancer cells. Disulfide bonds are important components in LOXL2, and they play a stabilizing role for protein structure or a functional role for regulating protein bioactivity. The redox potential of disulfide bond is one important property to determine the functional role of disulfide bond. In this study, we have calculated the reduction potential of all the disulfide bonds in LOXL2 by non-equilibrium alchemical simulations. Our results show that seven of seventeen disulfide bonds have high redox potentials between -182 and -298 mV and could have a functional role, viz., Cys573-Cys625, Cys579-Cys695, Cys657-Cys673, and Cys663-Cys685 in the catalytic domain, Cys351-Cys414, Cys464-Cys530, and Cys477-Cys543 in the scavenger receptor cysteine-rich (SRCR) domains. The disulfide bond of Cys351-Cys414 is predicted to play an allosteric function role, which could affect the metastasis and invasion of cancer cells. Other functional bonds have a catalytic role related to enzyme activity. The rest of disulfide bonds are predicted to play a structural role. Our study provides an important insight for the classification of disulfide bonds in LOXL2 and can be utilized for the drug design that targets the cysteine residues in LOXL2.

Role of Rho guanine nucleotide exchange factors in non-small cell lung cancer.

Conventionally, Rho guanine nucleotide exchange factors (GEFs) are known activators of Rho guanosine triphosphatases (GTPases) that promote tumorigenesis. However, the role of Rho GEFs in non-small cell lung cancer (NSCLC) remains largely unknown. Through the screening of 81 Rho GEFs for their expression profiles and correlations with survival, four of them were identified with strong significance for predicting the prognosis of NSCLC patients. The four Rho GEFs, namely ABR, PREX1, DOCK2 and DOCK4, were downregulated in NSCLC tissues compared to normal tissues. The downregulation of ABR, PREX1, DOCK2 and DOCK4, which can be attributfed to promoter methylation, is correlated with poor prognosis. The underexpression of the four key Rho GEFs might be related to the upregulation of MYC signaling and DNA repair pathways, leading to carcinogenesis and poor prognosis. Moreover, overexpression of ABR was shown to have a tumor-suppressive effect in PC9 and H1703 cells. In conclusion, the data reveal the unprecedented role of ABR as tumor suppressor in NSCLC. The previously unnoticed functions of Rho GEFs in NSCLC will inspire researchers to investigate the distinct roles of Rho GEFs in cancers, in order to provide critical strategies in clinical practice.

Paradoxical Roles of Desmosomal Components in Head and Neck Cancer.

Desmosomes are intercellular adhesion complexes involved in various aspects of epithelial pathophysiology, including tissue homeostasis, morphogenesis, and disease development. Recent studies have reported that the abnormal expression of various desmosomal components correlates with tumor progression and poor survival. In addition, desmosomes have been shown to act as a signaling platform to regulate the proliferation, invasion, migration, morphogenesis, and apoptosis of cancer cells. The occurrence and progression of head and neck cancer (HNC) is accompanied by abnormal expression of desmosomal components and loss of desmosome structure. However, the role of desmosomal components in the progression of HNC remains controversial. This review aims to provide an overview of recent developments showing the paradoxical roles of desmosomal components in tumor suppression and promotion. It offers valuable insights for HNC diagnosis and therapeutics development.

Lysyl oxidase-like 2 promotes esophageal squamous cell carcinoma cell migration independent of catalytic activity.

Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase (LOX) family that contributes to tumor cell metastasis. Our previous data identified two splice variants of LOXL2 (i.e., LOXL2 Δ72 and Δ13) in esophageal squamous cell carcinoma (ESCC) cells that increased cell invasiveness and migration but had lower LOX activities than wild-type LOXL2 (LOXL2 WT). We generated a series of LOXL2 deletion mutants with different deleted biochemical domains and examined the relationship between the cell migration abilities and catalytic activities, as well as subcellular locations, of these deletion mutants compared with LOXL2 WT in ESCC cells to explore the mechanism of LOXL2-driven ESCC cell migration. Our results indicated that the deletion mutants of LOXL2 had impaired deamination enzymatic activity; LOXL2 ΔSRCR4, which lacks the fourth scavenger receptor cysteine-rich (SRCR) domain, had lower enzymatic activity; and LOXL2 Y689F had no catalytic activity compared with LOXL2 WT. However these two mutants stimulated greater cellular migration than LOXL2 WT. Furthermore, the degree of cell migration promoted by LOXL2 ΔLO (in which the LOX-like domain was deleted) was higher than that of LOXL2 WT, and LOXL2 ΔSRCR3, which does not have the third SRCR domain, had lower LOX activity and cellular migration ability than LOXL2 WT. These results suggested that LOXL2 promotes ESCC cell migration independent of catalytic activity.

Network Analyses of the Differential Expression of Heat Shock Proteins in Glioma.

Heat shock protein (HSP) is a family of highly conserved protein, which exists widely in various organisms and has a variety of important physiological functions. Currently, there is no systematic analysis of HSPs in human glioma. The aim of this study was to investigate the characteristics of HSPs through constructing protein-protein interaction network (PPIN) considering the expression level of HSPs in glioma. After the identification of the differentially expressed HSPs in glioma tissues, a specific PPIN was constructed and found that there were many interactions between the differentially expressed HSPs in glioma. Subcellular localization analysis shows that HSPs and their interacting proteins distribute from the cell membrane to the nucleus in a multilayer structure. By functional enrichment analysis, gene ontology analysis, and Kyoto Encyclopedia of Genes and Genomes pathway analysis, the potential function of HSPs and two meaningful enrichment pathways was revealed. In addition, nine HSPs (DNAJA4, DNAJC6, DNAJC12, HSPA6, HSP90B1, DNAJB1, DNAJB6, DNAJC10, and SERPINH1) are prognostic markers for human brain glioma. These analyses provide a full view of HSPs about their expression, biological process, as well as clinical significance in glioma.

LOXL2 Upregulates Phosphorylation of Ezrin to Promote Cytoskeletal Reorganization and Tumor Cell Invasion.

Lysyl oxidase-like 2 (LOXL2), a copper-dependent enzyme of the lysyl oxidase family and its nonsecreted, catalytically dead spliced isoform L2Δ13, enhance cell migration and invasion, stimulate filopodia formation, modulate the expression of cytoskeletal genes, and promote tumor development and metastasis in vivo. We previously showed that LOXL2 reorganizes the actin cytoskeleton in esophageal squamous cell carcinoma (ESCC) cells, however, the underlying molecular mechanisms were not identified. Here, using interactome analysis, we identified ezrin (EZR), fascin (FSCN1), heat shock protein beta-1 (HSPB1), and tropomodulin-3 (TMOD3) as actin-binding proteins that associate with cytoplasmic LOXL2, as well as with its L2Δ13 variant. High levels of LOXL2 and L2Δ13 and their cytoskeletal partners correlated with poor clinical outcome in patients with ESCC. To better understand the significance of these interactions, we focused on the interaction of LOXL2 with ezrin. Phosphorylation of ezrin at T567 was greatly reduced following depletion of LOXL2 and was enhanced following LOXL2/L2Δ13 reexpression. Furthermore, LOXL2 depletion inhibited the ability of ezrin to promote tumor progression. These results suggest that LOXL2-induced ezrin phosphorylation, which also requires PKCα, is critical for LOXL2-induced cytoskeletal reorganization that subsequently promotes tumor cell invasion and metastasis in ESCC. In summary, we have characterized a novel molecular mechanism that mediates, in part, the protumorigenic activity of LOXL2. These findings may enable the future development of therapeutic agents targeting cytoplasmic LOXL2. SIGNIFICANCE: LOXL2 and its spliced isoform L2Δ13 promote cytoskeletal reorganization and invasion of esophageal cancer cells by interacting with cytoplasmic actin-binding proteins such as ezrin.

Clinical significance of LOXL4 expression and features of LOXL4-associated protein-protein interaction network in esophageal squamous cell carcinoma.

Lysyl oxidase-like 4 (LOXL4), a member of the LOX family proteins, catalyzes oxidative deamination of lysine residues in collagen and elastin, which are responsible for maintaining extracellular matrix homeostasis. In this study, the mRNA expression of LOXL4 in seven esophageal squamous cell carcinoma (ESCC) cell lines and 15 ESCC pairs of clinical samples were examined. Furthermore, LOXL4 protein levels in the ESCC cell lines were determined using western blotting. With the use of immunofluorescence, LOXL4 was observed to be localized primarily in the cytoplasm, but was also present in the nucleus. In addition, the results indicated that the upregulated expression of LOXL4 was associated with poor survival in patients with ESCC even following curative resection (P = 0.010). Similar Kaplan-Meier estimator curves for proteins that interact with LOXL4, SUV39H1 (P = 0.014) and COL2A1 (P = 0.011), were plotted. The analyses based on the protein-protein interaction network depicted the expression of LOXL4 and its associated proteins as well as their functions, suggesting that LOXL4 and its associated proteins may serve a significant role in the development and progression of ESCC. In conclusion, the results of the present study suggest that LOXL4 is a potential biomarker for patients with ESCC, as well as SUV39H1 and COL2A1, and high expression levels of these genes are associated with poor prognosis in patients with ESCC.

Diagnostic and prognostic value of serum L1-cell adhesion molecule in esophageal squamous cell carcinoma.

OBJECTIVE: L1 cell adhesion molecule (L1CAM) has been found to be dysregulated in several types of human cancers. Here, we aimed to determine the level of soluble L1CAM in serum of patients with esophageal squamous cell carcinoma (ESCC). METHODS: Serum levels of L1CAM were determined by an enzyme-linked immunosorbent assay (ELISA) in 191 patients with ESCC and 94 normal controls. Receiver operating characteristics (ROC) was employed to calculate diagnostic accuracy. Cumulative survival time was calculated by the Kaplan-Meier method and analyzed by the logrank test. RESULTS: Levels of L1CAM were significantly lower in all ESCC patients than in normal controls (P < 0.001). Detection of serum L1CAM provided a sensitivity of 28.3%, a specificity of 90.4% and an area under the curve (AUC) of 0.644 (95% CI: 0.579-0.710) in diagnosing ESCC. Similar results were observed in the diagnosis of early-stage ESCC (26.2% sensitivity, 90.4% specificity, and an AUC of 0.629). Moreover, decreased level of L1CAM was correlated with depth of tumor invasion (P < 0.05). Kaplan-Meier analysis showed that lower serum L1CAM level was significantly related to shorter overall survival time (P = 0.036) and disease-free survival time (P = 0.021) of ESCC patients. CONCLUSIONS: Our study demonstrated that serum L1CAM might serve as a potential biomarker for the diagnosis and prognosis of ESCC.

The protein-protein interaction network and clinical significance of heat-shock proteins in esophageal squamous cell carcinoma.

Heat-shock proteins (HSPs), one of the evolutionarily conserved protein families, are widely found in various organisms, and play important physiological functions. Nevertheless, HSPs have not been systematically analyzed in esophageal squamous cell carcinoma (ESCC). In this study, we applied the protein-protein interaction (PPI) network methodology to explore the characteristics of HSPs, and integrate their expression in ESCC. First, differentially expressed HSPs in ESCC were identified from our previous RNA-seq data. By constructing a specific PPI network, we found differentially expressed HSPs interacted with hundreds of neighboring proteins. Subcellular localization analyses demonstrated that HSPs and their interacting proteins distributed in multiple layers, from membrane to nucleus. Functional enrichment annotation analyses revealed known and potential functions for HSPs. KEGG pathway analyses identified four significant enrichment pathways. Moreover, three HSPs (DNAJC5B, HSPA1B, and HSPH1) could serve as promising targets for prognostic prediction in ESCC, suggesting these HSPs might play a significant role in the development of ESCC. These multiple bioinformatics analyses have provided a comprehensive view of the roles of heat-shock proteins in esophageal squamous cell carcinoma.

The arachidonic acid metabolism protein-protein interaction network and its expression pattern in esophageal diseases.

Arachidonic acid (AA) and its metabolites are involved in the development and progression of inflammation and tumors in various tissues. We investigated the protein-protein interaction network (PPIN) of key enzymes in AA metabolism and their interacting proteins, as well as their expression patterns in different types of esophageal disease, involving esophagitis, Barrett's esophagus, adenocarcinoma and squamous cell carcinoma. PPINs were constructed to illustrate the key enzymes and their interacting proteins along the metabolic cascade. The network also showed key enzymes that could connect or cross-talk with at least one partner protein. The inflammation-related gene RELA (NF-kB) was found to interact with both PLA2G4A and ALOX5. Expression levels of the PPIN proteins, as well as their expression correlations, in different esophageal diseases were analyzed and integrated into the PPIN to illustrate a dynamic change. At least six significant pairs of expression relationships were identified across different esophageal diseases. The expression levels of eight enzymes (ALOX5, ALOX5AP, CYP2C8, CYP4F11, LTA4H, PLA2G4A, CYP2D6, PTGES2) correlated with the survival time of ESCC patients. In summary, we constructed an AA metabolic PPIN to explore AA metabolism-related gene expression patterns in esophageal diseases, showing their dynamic change and potential for therapeutic targeting from inflammation to cancer.

Network analyses elucidate the role of SMYD3 in esophageal squamous cell carcinoma.

SMYD3 is a member of the SET and myeloid-Nervy-DEAF-1 (MYND) domain-containing protein family of methyltransferases, which are known to play critical roles in carcinogenesis. Expression of SMYD3 is elevated in various cancers, including esophageal squamous cell carcinoma (ESCC), and is correlated with the survival time of patients with ESCC. Here, we dissect gene expression data, from a previously described KYSE150 ESCC cell line in which SMYD3 had been knocked down, by integration with the protein-protein interaction (PPI) network, to find the new potential biological roles of SMYD3 and subsequent target genes. By construction of a specific PPI network, differentially expressed genes (DEGs), following SMYD3 knockdown, were identified as interacting with thousands of neighboring proteins. Enrichment analyses from the DAVID Functional Annotation Chart found significant Gene Ontology (GO) terms associated with transcription activities, which were closely related to SMYD3 function. For example, YAP1 and GATA3 might be a target gene for SMYD3 to regulate transcription. Enrichment annotation of the total DEG PPI network by GO 'Biological Process' generated a connected functional map and found 532 significant terms, including known and potential biological roles of SMYD3 protein, such as expression regulation, signal transduction, cell cycle, cell metastasis, and invasion. Subcellular localization analyses found that DEGs and their interacting proteins were distributed in multiple layers, which might reflect the intricate biological processes at the spatial level. Our analysis of the PPI network has provided important clues for future detection of the biological roles and mechanisms, as well as the target genes of SMYD3.