Menthol induces apoptosis and inhibits proliferation and migration of nonsmall cell lung carcinoma in vitro and in vivo through Akt pathway.

BACKGROUND: About 40% of nonsmall cell lung cancers (NSCLCs) have already progressed in an advanced stage at the time of diagnosis. Development of effective prevention and therapy approaches against NSCLC is critical for reducing mortality. As a fundamental ingredient of peppermint oil, menthol has been demonstrated to possess an antitumor activity in several types of carcinomas. However, the potential role of menthol on NSCLC has not been reported. The present study aims to investigate the effect and underlying mechanism of menthol on proliferation, apoptosis, and mobility of human lung adenocarcinoma. METHODS: Cell apoptosis was examined by MTT and flow cytometry. The motility of cells was determined by Transwell assay. Western blot analysis was performed to determine expression level of proteins. In vivo model of nude mice was established for evaluating the influence of menthol on tumorigenicity of A549 cells. The expression lentiviral vector of Akt was established in NSCLC cells for further verifying the inhibiting effect of menthol on survival and mobility of NSCLC cells via Akt pathway. RESULTS: The results showed that menthol promoted A549 cell apoptosis, suppressed cell proliferation, and motility by altering the phosphorylated protein level of Akt. Menthol enhanced the expression level of Bax while decreasing expression of Bcl-2, Caspase-3, and MMPs proteins. In vivo experiments suggested that menthol exhibited an inhibitory effect in tumor growth on xenografts. These results were further validated in Akt over-expressed A549 and H1299 cells. CONCLUSIONS: Menthol could display an inhibitory effect on NSCLC cells through Akt signaling pathway, making it a potential target for NSCLC treatment.

Frequency comb with a spectral range of 0.4-5.2†µm based on a compact all-fiber laser and LiNbO3 waveguide.

This Letter presents a 0.4-5.2-µm frequency comb from a compact laser. We designed an integrated fiber device for a figure-9 laser and constructed an all-fiber laser system. The spectrum of the fiber laser was scaled to the broadband region using a chirped periodically poled lithium niobate waveguide. To use this system for gas sensing, a mid-infrared comb with a spectral range of 2.5-5.2 µm and average power of 2.1 mW was divided using an optical filter. The optical part was packaged in a 305 mm × 225 mm × 62 mm box. The comb was stabilized by locking the repetition rate and carrier-envelope offset frequency of the seed source. The system provided an ultrabroadband spectral range from 0.4 to 5.2 µm, which could be applied to spectroscopy, frequency metrology, and optical synthesizers.

TRIM25-mediated ubiquitination of G3BP1 regulates the proliferation and migration of human neuroblastoma cells.

Neuroblastoma is one of the most severe malignant tumors and accounts for substantial cancer-related mortality in children. Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is highly expressed in various cancers and acts as an important biomarker of poor prognosis. The ablation of G3BP1 inhibited the proliferation and migration of human SHSY5Y cells. Because of its important role in neuroblastoma, the regulation of G3BP1 protein homeostasis was probed. TRIM25, which belongs to the tripartite motif (TRIM) family of proteins, was identified as an interacting partner for G3BP1 using the yeast two-hybrid (Y2H) method. TRIM25 mediates the ubiquitination of G3BP1 at multiple sites and stabilizes its protein level. Then, our study found that TRIM25 knockdown also inhibited the proliferation and migration of neuroblastoma cells. The TRIM25 and G3BP1 double knockdown SHSY5Y cell line was generated, and double knockdown cells exhibited lower proliferation and migration ability than cells with only TRIM25 or G3BP1 knockdown. Further study demonstrated that TRIM25 promotes the proliferation and migration of neuroblastoma cells in a G3BP1-dependent manner. Tumor xenograft assays indicated that the ablation of TRIM25 and G3BP1 synergistically suppressed the tumorigenicity of neuroblastoma cells in nude mice, and TRIM25 promoted the tumorigenicity of G3BP1 intact SHSY5Y cells but not G3BP1 knockout cells. Thus, TRIM25 and G3BP1, two oncogenic genes, are suggested as potential therapeutic targets for neuroblastoma.

Hsa_circ_0007031 promotes the proliferation and migration of osteosarcoma cells by sponging miR-196a-5p to regulate the HOXB6.

Circular RNAs (circRNAs), a subclass of noncoding RNAs, have been demonstrated to play an essential role in osteosarcoma (OS) development. However, there is still a significant gap in investigating its biological functions and underlying molecular mechanisms, and novel targets of circRNAs have yet to be fully explored. Herein, we found that hsa_circ_0007031 is noticeably raised in OS clinical tissues and cell lines. Hsa_circ_0007031 accelerates OS cell proliferation and migration in vitro and tumor growth and metastasis in vivo and is strongly linked with the stemness of cancer stem cells in OS. Mechanistically, hsa_circ_0007031 shares miRNA response elements with Homeobox B6 (HOXB6), which is identified as a novel pro-tumorigenic gene of OS. Hsa_circ_0007031 competitively binds to miR-196a-5p to prevent miR-196a-5p from lowering the level of HOXB6, which modulates chemokines of cytokine-cytokine receptor interaction signaling pathway and finally promotes OS malignant behavior. In summary, our data unveiled that hsa_circ_0007031/miR-196a-5p/HOXB6 axis-mediated cytokine-cytokine receptor interaction facilitates the progression of OS and maintains the properties of tumor stem cells, which could be a promising therapeutic target for OS.

Molecular fingerprints of nuclear genome and mitochondrial genome for early diagnosis of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer with high morbidity and mortality rates. Due to the heterogeneity of LUAD, its characteristics remain poorly understood. Exploring the clinical and molecular characteristics of LUAD is challenging but vital for early diagnosis. METHODS: This observational and validation study enrolled 80 patients and 13 healthy controls. Nuclear and mtDNA-captured sequencings were performed. RESULTS: This study identified a spectrum of nuclear and mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with diagnosis. The correlation coefficient for somatic mutations in cfDNA and patient-matched tumor tissues was high in nuclear and mitochondrial genomes. The mutation number of highly mutated genes was evaluated, and the Least Absolute Shrinkage and Selection Operator (LASSO) established a diagnostic model. Receiver operating characteristic (ROC) curve analysis explored the diagnostic ability of the two panels. All models were verified in the testing cohort, and the mtDNA panel demonstrated excellent performance. This study identified somatic mutations in the nuclear and mitochondrial genomes, and detecting mutations in cfDNA displayed good diagnostic performance for early-stage LUAD. Moreover, detecting somatic mutations in the mitochondria may be a better tool for diagnosing early-stage LUAD. CONCLUSIONS: This study identified specific and sensitive diagnostic biomarkers for early-stage LUAD by focusing on nuclear and mitochondrial genome mutations. This also further developed an early-stage LUAD-specific mutation gene panel for clinical utility. This study established a foundation for further investigation of LUAD molecular pathogenesis.

The value of completion residual lung resection in ipsilateral recurrent non-small cell lung cancer.

Background: Recurrence is one of the most important challenges to manage lung cancer. Selected patients might be candidates for resection. This study assessed the outcomes and hazard factors of patients after completion of lung resection for recurrence, focusing specifically on postrecurrence survival (PRS) and overall survival (OS) after surgery. Methods: This retrospective study enrolled 63 patients who underwent complete pulmonary resection for recurrence between January 2015 and December 2018. Inclusion criteria include potentially curative first resection for primary lung cancer, histologically proven recurrent or new malignancy, and complete pathological report after both operations. PRS and OS were assessed and the influence of patient and treatment features on these endpoints was evaluated. Results: Most of the patients recurred at stage IIIA, and nearly three-fourth received complete pneumonectomy. The overall 2- and 5-year survival rates were 95% and 75%, whereas the overall 2- and 5-year postrecurrence survival rates were 55% and 36%, respectively. No patient died within 30 or 90 days after completion of residual lung resection, and no serious complications occurred during follow-up. Upon selection of clinically important variables by the Cox proportional hazards regression model, the r-stage [hazard ratio (HR), 3.35; 95% CI, 1.11-10.10; P = 0.03] and stage of primary tumor (HR, 6.26; 95% CI, 2.00-19.55; P < 0.01) were hazard factors for PRS and OS respectively. Conclusions: Complete pulmonary resection is an acceptable option in selected patients with recurrent lung cancer after surgery. The patients with r-stage earlier than IIIA may benefit from completion pulmonary resection but not IIIB. Completion pneumonectomy failed to significantly prolong the OS. The OS in the enrolled cases was mainly affected by the p-TNM stage assessed by the first resection for primary lung cancer.

Identification of Candidate MicroRNA-mRNA Subnetwork for Predicting the Osteosarcoma Progression by Bioinformatics Analysis.

Osteosarcoma (OS) is the pretty common primary cancer of the bone among the malignancies in adolescents. A single molecular component or a limited number of molecules is insufficient as a predictive biomarker of OS progression. Hence, it is necessary to find novel network biomarkers to improve the prediction and therapeutic effect for OS. Here, we identified 230 DE-miRNAs and 821 DE-mRNAs through two miRNA expression-profiling datasets and three mRNA expression-profiling datasets. We found that hsa-miR-494 is closely linked with the survival of OS patients. In addition, we analyzed GO and KEGG enrichment for targets of hsa-miR-494-5p and hsa-miR-494-3p through R programming. And five mRNAs were predicted as common targets of hsa-miR-494-5p and hsa-miR-494-3p. We further revealed that upregulated TRPS1 was strongly correlated with poor outcomes in OS patients through the survival analysis based on the TARGET database. The qRT-PCR study verified that the expression of hsa-miR-494-5p and hsa-miR-494-3p was declined considerably, while TRPS1 was notably raised in OS cells when compared to the osteoblasts. Thus, we generated a new regulatory subnetwork of key miRNAs and target mRNAs using Cytoscape software. These results indicate that the novel miRNA-mRNA subnetwork composed of hsa-miR-494-5p, hsa-miR-494-3p, and TRPS1 might be a characteristic molecule for assessing the prognostic value of OS patients.

Toxic effects and transcriptional responses in zebrafish liver cells following perfluorooctanoic acid exposure.

As a typical type of persistent organic pollutant, perfluorooctanoic acid (PFOA) is pervasive in the environment. Multiple studies have found that PFOA has hepatotoxicity, but the mechanism remains poorly understood. In this study, the toxic effects of different concentrations of PFOA on zebrafish liver cells were systematically assessed by recording cell survival, ultrastructural observations, and transcriptome analyses. The results showed that the inhibition of cell viability and the massive accumulation of autophagic vacuoles were observed at 400 µM PFOA, while transcriptomic changes occurred with treatments of 1 and 400 µM PFOA. The transcription levels of 1055 (977 up- and 78 down-regulated genes) and 520 (446 up- and 74 down-regulated genes) genes were significantly changed after treatment with 1 and 400 µM PFOA, respectively. Based on Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, significant expression changes were observed in autophagy, tight junction, signal transduction, immune system, endocrine system, and metabolism-related pathways, indicating that such processes were greatly affected by PFOA exposure. The findings of this study will provide a scientific basis for the toxic effects and potential toxic mechanisms of PFOA on zebrafish, and provide information for ecological risk assessments.

LncRNA UCA1 accelerates osteosarcoma progression via miR-145 and Wnt/ß-catenin pathway.

Long non-coding (lnc) urothelial cancer associated 1 (UCA1) has been confirmed to participate in osteosarcoma (OS), but its specific mechanism is still under investigation. The study was designed to reveal the interaction between UCA1 and its downstream effector molecules, so as to determine whether there is any interaction of regulating physiological processes in tumor cells. Here, we studied the signaling cascade involving UCA1, miR-145, and HMGA1. The expression of UCA1 and miR-145 levels was interfered to assess their effects on physiological processes of tumor cells. The relationship between UCA1 and miR-145 as well as between HMGA1 and miR-145 was identified by the dual-luciferase reporter (DLR) assay, and the in vivo effect of UCA1 was estimated in nude mouse xenografts. As a result, a negative association was found between UCA1 and miR-145 in OS cells. Both UCA1 knockout and miR-145 over-expression inhibited malignant progression and induced apoptosis in MG-63 and U2OS cells. UCA1 knockout led to an increase in miR-145 and decreases in HMGA1, p-ß-catenin and cyclin D1. In addition, UCA1 upregulation promoted tumor growth in vitro and changed miR-145 and HMGA1 levels in vivo. Moreover, the DLR assay and RNA immunoprecipitation (RIP) showed that UCA1 was likely to regulate HMGA1 levels by sponging miR-145. Overall, the inhibition of UCA1 increases miR-145 levels and decreases HMGA1 levels, thereby exerting an anti-tumor role in OS.

N6-Methyladenosine Reader YTHDF2 Enhances Non-Small-Cell Lung Cancer Cell Proliferation and Metastasis through Mediating circ_SFMBT2 Degradation.

Objective: circ_SFMBT2 was reported to facilitate malignant progression in various cancers, but its function in non-small-cell lung cancer (NSCLC) has not been fully uncovered. This study aimed to investigate the effects of N6-methyladenosine (m6A) methylation of circ_SFMBT2 (circ_0017628) on non-small-cell lung cancer (NSCLC) and its underlying mechanisms. Methods: Paired tumor and noncancerous tissues from NSCLC patients were surgically collected from January 2020 to March 2021 in our hospital. The levels of circ_SFMBT2 and LATS2 in NSCLC and human bronchial epithelial cells were assayed with qRT-PCR. Overexpression or silencing of circ_SFMBT2, LATS2, or YTHDF2 was performed in the NSCLC cells. CCK-8, colony-forming, and transwell assays were performed to analyze cell proliferation, viability, and migration, respectively. Meanwhile, the expression of MMP-9, E-cadherin, vimentin, and the Hippo/YAP pathway components was examined by western blotting. The m6A enrichment in circ_SFMBT2 was verified using methylated RNA immunoprecipitation, and interaction between circ_SFMBT2 and YTHDF2 was assessed by RNA pull-down and immunoprecipitation assays. Results: Both circ_SFMBT2 and LATS2 were lowly expressed in NSCLC cells and tissues. A positive correlation of circ_SFMBT2 with LATS2 was identified, and circ_SFMBT2 was localized predominantly in the cytoplasm. circ_SFMBT2 overexpression negatively regulated cell proliferation, viability, migration, and epithelial-mesenchymal transition while promoting the Hippo/YAP pathway activation. Notably, knockdown of LATS2 effectively abrogated the inhibitory effects of circ_SFMBT2 overexpression on NSCLC cell malignancies. Besides, m6A was specifically enriched in circ_SFMBT2, and circ_SFMBT2 could bind to YTHDF2. Silencing of YTHDF2 led to an increase in circ_SFMBT2 expression while inhibiting the malignancy of cancer cells. Conclusion: Our results showed that YTHDF2 could facilitate NSCLC cell proliferation and metastasis via the Hippo/YAP pathway activation by mediating circ_SFMBT2 degradation.

Dysbiosis of the Gut Microbiome Is Associated With Histopathology of Lung Cancer.

Lung cancer is a malignancy with high incidence and mortality worldwide. Previous studies have shown that the gut microbiome plays an important role in the development and progression of metabolic cancers. However, data on the characteristics of the gut microbiome with different histopathology types of lung cancer remain scant. We collected stool samples from 28 healthy people (HP) and 61 lung cancer patients. The lung cancer patients were classified into three types according to their histopathology: Atypical Adenomatous Hyperplasia/Adenocarcinoma in situ (AAH/AIS), Minimally Invasive Adenocarcinoma (MIA), and Invasive Adenocarcinoma (IA). In addition, we employed 16S rRNA gene amplicon sequencing to analyze the characteristics of the gut microbiome in these patients. Our analysis revealed that the categorized cancer patients had unique intestinal flora characteristics, and had lower density and flora diversity compared to healthy people. Besides, the structure of the flora families and genera was more complex, and each group presented specific pathogenic microbiota. The patients in the AAH/AIS group and HP group had relatively similar flora structure compared with the IA and MIA groups. In addition, we identified several flora markers that showed significant changes with the development of lung cancer. Lung cancer gut microbiota showed a decrease in short-chain fatty acids (SCFAs) producing and anti-inflammatory bacteria compared to healthy people, while some pathogenic bacteria such as proinflammatory or tumor-promoting bacteria were more abundant in lung cancer patients. On the other hand, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Clusters of Orthologous Group (COG) annotation demonstrated suppression of some dominant metabolism-related pathways in lung cancer. These findings provide new biomarkers for the diagnosis and prognostic assessment of lung cancer and lay the basis for novel targeted therapeutic strategies for the prevention and treatment of lung cancer. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03244605].

Combined Consideration of Tumor-Associated Immune Cell Density and Immune Checkpoint Expression in the Peritumoral Microenvironment for Prognostic Stratification of Non-Small-Cell Lung Cancer Patients.

Given the complexity and highly heterogeneous nature of the microenvironment and its effects on antitumor immunity and cancer immune evasion, the prognostic value of a single immune marker is limited. Here, we show how the integration of immune checkpoint molecule expression and tumor-associated immune cell distribution patterns can influence prognosis prediction in non-small-cell lung cancer (NSCLC) patients. We analyzed tissue microarray (TMA) data derived from multiplex immunohistochemistry results and measured the densities of tumor-infiltrating CD8+ and FOXP3+ immune cells and tumor cells (PanCK+), as well as the densities of programmed cell death 1 (PD-1)+ and programmed cell death ligand 1 (PD-L1)+ cells in the peritumor and intratumor subregions. We found a higher density of infiltrating CD8+ and FOXP3+ immune cells in the peritumoral compartment than in the intratumoral compartment. In addition, unsupervised hierarchical clustering analysis of these markers revealed that the combination of high CD8/FOXP3 expression, low PD-1 and PD-L1 immune checkpoint expression, and lack of epidermal growth factor receptor (EGFR) mutation could be a favorable predictive marker. On the other hand, based on the clustering analysis, low CD8/FOXP3 and immune checkpoint (PD-1 and PD-L1) expression might be a marker for patients who are likely to respond to strategies targeting regulatory T (Treg) cells. Furthermore, an immune risk score model was established based on multivariate Cox regression, and the risk score was determined to be an independent prognostic factor for NSCLC patients. These results indicate that the immune context is heterogeneous because of the complex interactions of different components and that using multiple factors in combination might be promising for predicting the prognosis of and stratifying NSCLC patients.

Analysis and identification of m6A RNA methylation regulators in metastatic osteosarcoma.

Osteosarcoma (OS) is characterized by rapid growth and early metastasis. However, its mechanism remains unclear. N6-methyladenosine (m6A) modification and its regulatory factors play essential roles in most cancers, including OS. In this study, we screened out 21 m6A modifiers using the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, followed by the identification of the critical m6A methylation modifiers. The results revealed that the expression levels of three m6A methylation regulators, namely RBM15, METTL3, and LRPPRC, were associated with the low survival rate of patients with OS. We further studied the independent prognostic factors by performing univariate and multivariate Cox analyses and found that metastasis was an independent prognostic factor for patients with OS. Furthermore, we found for the first time that RBM15 was specific for metastatic OS rather than non-metastatic OS. Moreover, the significant overexpression of RBM15 was validated in metastatic OS cell lines and in actual human clinical specimens. We also revealed that RBM15 promoted the invasion, migration, and metastasis of OS cells through loss-functional and gain-functional experiments and an animal metastatic model. In conclusion, RBM15 has a high correlation with OS metastasis formation and the decreased survival rate of patients with OS, and this may serve as a useful biomarker for predicting metastasis and prognosis of patients with OS.

Cloning and characterisation of a Δ9 fatty acyl desaturase-like gene from the red claw crayfish (Cherax quadricarinatus) and its expression analysis under cold stress.

Desaturase is one of the key enzymes in the unsaturated fatty acid synthesis pathway. Δ9 desaturase catalyzes the synthesis of oleic acid from stearic acid by introducing double bonds in the 9th and 10th carbon chains, thereby increasing the content of MUFAs in the body. In order to explore the main function of the Δ9 desaturase gene under low temperature stress, RACE-PCR technology was used in this study to clone the full-length sequence of the CqFAD9-like from the hepatopancreas of red claw crayfish, Cherax quadricarinatus. The full length of the sequence is 1236 bp, and the open reading frame is 1041 bp, encoding 346 amino acid residues. The 5 'UTR is 116 bp, the 3' UTR is 79 bp, and the 3 'UTR contains a PloyA tail. The predicted theoretical isoelectric point and molecular weight are 8.68 and 40.28 kDa, respectively. Homology analysis showed that the sequence had the highest similarity with FAD9 from crustaceans. The results of real-time PCR showed that the expression level of this gene was highest in the hepatopancreas, which was significantly higher than other tissues, followed by the ovaries, brain ganglion and stomach. At the same time, the expression of the CqFAD9-like in hepatopancreas of crayfish cultured at 25, 20, 15 and 9 °C for four weeks was detected. The results showed that expression of the FAD9 gene increased gradually with decreasing temperature, indicating that metabolic desaturation might play a regulatory role during cold stress.

U.S. Children and Youth's Physical Activities Inside and Outside of School PE: 1985 vs. 2012.

The purpose of this study was, by taking advantage of the rich data from two U.S. national fitness surveys, to examine the physical activity (PA) students engaged in, both inside and outside school physical education (PE), determine if there are differences by grade, sex, and weight status, and if there was a change between 1985 and 2012. The data from the 1985 National Children and Youth Fitness Study (NCYFS) and the 2012 NHANES National Youth Fitness Survey (NNYFS) were matched, merged (N = 6178, 3107 boys and 3071 girls), and analyzed. It was found that basketball remained the most popular PA inside school PE across both surveys. Swimming was the most popular PA outside of school PE in 1985, but was replaced by running in 2012. Although PA taught and promoted inside of school PE and that such PA practiced outside were moderately correlated across the surveys, some disconnections were noticed. The impact of grade, sex, and weight status on PA preference and participation was also confirmed. What is needed is to the design and integration of more lifelong and individual PAs in future school PE curricula and school and community children and youth sport and PA programs.

Integrative findings indicate anti-tumor biotargets and molecular mechanisms of calycosin against osteosarcoma.

Calycosin is reportedly evidenced with pharmacologically treating bone cells. However, the comprehensive anti-osteosarcoma (OS) mechanisms of calycosin have not been uncovered. By using a systemic method of network pharmacology, the present study aimed to reveal potential anti-OS biotargets and molecular mechanisms played by calycosin. Moreover, human and animal experiments were conducted to verify the core biotargets of calycosin against OS. As results, all primary and core biotargets, biological processes, molecular pathways of calycosin against OS were revealed. Additionally, top 20 biological processes and pathways of calycosin against OS were identified. In human study, the OS sections resulted in reduced expressions of tumor protein p53 (TP53), Caspase-3 (CASP3), and elevated X-linked inhibitor of apoptosis protein (XIAP) expression in comparison with OS-free controls. As shown in cell culture study, calycosin-treated OS cells showed reduced cell proliferation, and promoted cell apoptosis. In TUNEL stains, calycosin resulted in elevated apoptotic cells. As showed in immunostaining, calycosin-treated OS cells exhibited intracellular up-regulation of TP53, CASP3 expressions, and decreased XIAP expressions. Taken together, the biological informational findings manifest the candidate and core biotargets, molecular functions and pathways of calycosin against OS. Attractively, these core biotargets may be used for effectively detecting and treating human OS.

A Novel Prognostic Model of Early-Stage Lung Adenocarcinoma Integrating Methylation and Immune Biomarkers.

Lung adenocarcinoma (LUAD) is caused by multiple biological factors. Therefore, it will be more meaningful to study the prognosis from the perspective of omics integration. Given the significance of epigenetic modification and immunity in tumorigenesis and development, we tried to combine aberrant methylation and tumor infiltration CD8 T cell-related genes to build a prognostic model, to explore the key biomarkers of early-stage LUAD. On the basis of RNA-seq and methylation microarray data downloaded from The Cancer Genome Atlas (TCGA), differentially expressed genes and aberrant methylated genes were calculated with "DEseq2" and "ChAMP" packages, respectively. A Chi-square test was performed to obtain methylation driver genes. Weighted correlation network analysis (WGCNA) was utilized to mine cancer biomarkers related to CD8 T cells. With the consequences of univariate Cox proportional hazards analysis and least absolute shrinkage and selection operator (LASSO) COX regression analysis, the prognostic index based on 17 methylation driver genes (ZNF677, FAM83A, TRIM58, CLDN6, NKD1, NFE2L3, FKBP5, ITGA5, ASCL2, SLC24A4, WNT3A, TMEM171, PTPRH, ITPKB, ITGA2, SLC6A17, and CCDC81) and four CD8 T cell-related genes (SPDL1, E2F7, TK1, and TYMS) was successfully established, which could make valuable predictions for the survival risk of patients with early-stage LUAD.

Ubiquitination of NOTCH2 by DTX3 suppresses the proliferation and migration of human esophageal carcinoma.

The NOTCH2 gene plays a role in the development of many tumors. Deltex E3 ubiquitin ligase 3 (DTX3) was identified as a novel E3 ligase for NOTCH2 and as a potential therapeutic target for esophageal cancer. However, whether DTX3 could regulate NOTCH2 to suppress the progression of esophageal carcinoma remains unknown. In our study, NOTCH2 had higher expression in human esophageal carcinoma cell lines compared to normal human esophageal epithelial cell line, and ablation of NOTCH2 suppressed the proliferation and migration of esophageal carcinoma cells. A novel E3 ligase for NOTCH2 was identified by yeast two-hybrid (Y2H) screening, and DTX3 promoted the ubiquitination and degradation of NOTCH2. Further study showed that DTX3 overexpression suppressed the proliferation and tumorigenicity of human oesophageal carcinoma cells. The analysis of tissue samples from patients revealed that the expression of NOTCH2 was high while the expression of DTX3 was low in esophageal cancer. Furthermore, the expression of DTX3 and NOTCH2 showed a significant negative correlation in human oesophageal cancer samples. Our study suggested that the DTX3-NOTCH2 axis plays an important role in the progression of esophageal cancer, and DTX3 acts as an anti-oncogene in esophageal carcinoma, potentially offering a therapeutic target for esophageal cancer.