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Cancer Innovation Aug 2024Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor...
BACKGROUND
Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required.
METHODS
The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms.
RESULTS
NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC.
CONCLUSIONS
NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.
PubMed: 38948253
DOI: 10.1002/cai2.122 -
Journal of Cancer 2024Breast cancer (BC) is the most common tumor in women worldwide. TRIM28 (RNF96) plays pleiotropic biological functions, such as silencing target genes, facilitating DNA...
Breast cancer (BC) is the most common tumor in women worldwide. TRIM28 (RNF96) plays pleiotropic biological functions, such as silencing target genes, facilitating DNA repair, stimulating cellular proliferation and differentiation, and contributing to cancer progression. TRIM28 plays an increasingly crucial role in cancer, but its impact on BC, including breast invasive carcinoma, remains poorly understood. In the current study, analyses of online databases, quantitative real-time quantitative PCR, immunohistochemistry, and western blotting were performed on patients with breast invasive carcinoma (BRCA). Cordycepin (CD) was used to monitor BC progression and TRIM28 expression . As a result, we observed that TRIM28 is highly expressed in breast invasive carcinoma tissues compared with the corresponding normal tissues and is correlated with metastatic / invasive progression. High expression of TRIM28 might serve as a prognostic marker for long-term survival in triple-negative BC, advanced BC, or breast invasive carcinoma. Although TRIM28 methylation in tumor tissues of breast invasive carcinoma is not significantly changed compared to the matched normal tissues, the expressions and methylation of TRIM28 are significantly reversely correlated. TRIM28 expression was inhibited by CD in the mouse model, indicating its role in preventing BC progression. Thus, TRIM28 might be a potentially valuable molecular target for forecasting the progression / prognosis of patients with breast invasive carcinoma. CD, which represses BC growth/metastasis, may be involved partially through suppressing TRIM28 expression.
PubMed: 38947392
DOI: 10.7150/jca.95876 -
Journal of Cancer 2024Advanced-stage ovarian cancer (OC) is among the most fatal female genital tract neoplasms worldwide. Although different genetic mechanisms have been shown to be...
Advanced-stage ovarian cancer (OC) is among the most fatal female genital tract neoplasms worldwide. Although different genetic mechanisms have been shown to be involved in ovarian carcinogenesis, the role of introns methylation is still unresolved. We performed methylation analysis of introns 1, 3, and 4 of the to identify patterns in primary stage III OCs, corresponding metastases, and healthy tissues. The study involved samples of paraffin-embedded tissues obtained from 80 patients with stage III OCs, who underwent surgery at the Department of Gynecology and Gynecologic Oncology of the Military Institute of Medicine in Warsaw, Poland. Altogether, 40 serous-type G2/3 OCs and 40 endometrioid-type G2/3 OCs were included. From the same patient, metastatic and normal tissues were simultaneously analyzed. As a control group, 80 tissue samples were collected from patients after bariatric operations. Human ovarian cancer A2780 cell line was also investigated. Total genomic DNA was isolated from paraffin-embedded tissue blocks and the methylation analysis was performed by bisulfite DNA conversion, DNA amplification with specific primers, cloning, and DNA sequencing. All of the samples of intron 1 of were un-methylated in OCs, metastatic tissues, and in healthy tissues from the same patient. Also, no methylation of intron 1 was detected in cells from the human A2780 ovarian cancer cell line and in all samples from control group. In all samples, introns 3 and 4 of the were methylated in primary tumors, metastatic tissue, and in healthy tissue from the same patient, in human A2780 ovarian cell line, and in DNA samples from healthy patients. None of the clinicopatholocal features was related to the introns methylation status. Our data on introns methylation sheds new light on the mechanism of p53 activity for a better understanding of cancer biology. The study suggests the existence of an additional regulation rule of activity that involves demethylation-methylation mechanisms. Methylation at introns 3 and 4 may also overall help in protecting against damage by viral restrictases or viral DNA integration.
PubMed: 38947384
DOI: 10.7150/jca.94945 -
Journal of Cancer 2024Hepatocellular carcinoma (HCC) is the main type of primary liver cancer, and its related death ranks third worldwide. The curative methods and progress prediction...
Hepatocellular carcinoma (HCC) is the main type of primary liver cancer, and its related death ranks third worldwide. The curative methods and progress prediction markers of HCC are not sufficient enough. Nevertheless, little progress has been made in the signature of mA-, mC-, mA-, mG-, and DNA methylation of HCC. We calibrated a risk gene signature model that can be used to categorize HCC patients based on univariate, multivariate, and LASSO Cox regression analysis. This gene signature classified the patients into high- and low-risk subgroups. Patients in the high-risk group showed significantly reduced overall survival (OS) compared with patients in the low-risk group. The gene set variation analysis (GSVA), immune infiltration, and immunotherapy response were analyzed. The results demonstrated that an immunosuppressive environment was exited and the high-risk group had higher sensitivity to 5-fluorouracil, cisplatin, sorafenib, tamoxifen, and epirubicin. These results indicated personalized therapy should be taken into consideration. Our findings enriched our understanding of the molecular heterogeneity, tumor microenvironment (TME), and drug susceptibility of HCC. mA-, mC-, mA-, mG-, and DNA methylation-related regulators may be promising biomarkers for future research.
PubMed: 38947378
DOI: 10.7150/jca.95730 -
Research Square Jun 2024Background Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological...
Background Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk. Limited by available data, most studies investigating these relationships have been cross-sectional - using a single EA measurement. However, the recent growth in longitudinal DNAm studies has led to analyses of associations with EA over time. These studies differ in (i) their choice of model; (ii) the primary outcome (EA vs. EAA); and (iii) in their use of chronological age or age-independent time variables to account for the temporal dynamic. We evaluated the robustness of each approach using simulations and tested our results in two real-world examples, using biological sex and birthweight as predictors of longitudinal EA. Results Our simulations showed most accurate effect sizes in a linear mixed model or generalized estimating equation, using chronological age as the time variable. The use of EA versus EAA as an outcome did not strongly impact estimates. Applying the optimal model in real-world data uncovered an accelerated EA rate in males and an advanced EA that decelerates over time in children with higher birthweight. Conclusion Our results can serve as a guide for forthcoming longitudinal EA studies, aiding in methodological decisions that may determine whether an association is accurately estimated, overestimated, or potentially overlooked.
PubMed: 38947070
DOI: 10.21203/rs.3.rs-4482915/v1 -
Research Square Jun 2024Background DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes...
Background DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes are less well-defined. Objective To examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation. Methods Peripheral blood T cells from 35 adults with asthma in Beijing, China were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores. Results Significant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included , several members of the family, , , , and several genes downstream of the and signaling pathway. Conclusion These findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to the phenotype and severity of their overall disease.
PubMed: 38946998
DOI: 10.21203/rs.3.rs-4476948/v1 -
Research Square Jun 2024Background The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha...
Background The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown. Methods Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC and , respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry. Results ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth and . Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways. Conclusion DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.
PubMed: 38946977
DOI: 10.21203/rs.3.rs-4451060/v1 -
MedRxiv : the Preprint Server For... Jun 2024Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows...
Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in etiological interpretations. Here, we apply an integrated approach combining Mendelian Randomization and twin-based Direction-of-Causation analyses (MR-DoC) to examine causality underlying smoking-associated blood DNAm changes in the Netherlands Twin Register (N=2577). Evidence across models suggests that current smoking's causal effects on DNAm likely drive many of the previous EWAS findings, implicating functional pathways relevant to several adverse health outcomes of smoking, including hemopoiesis, cell- and neuro-development, and immune regulation. Additionally, we find evidence of potential reverse causal influences at some DNAm sites, with 17 of these sites enriched for gene regulatory functional elements in the brain. The top three sites with evidence of DNAm's effects on smoking annotate to genes involved in G protein-coupled receptor signaling (, ) and innate immune response (), elucidating potential biological risk factors for smoking. This study highlights the utility of integrating genotypic and DNAm measures in twin cohorts to clarify the causal relationships between health behaviors and blood DNAm.
PubMed: 38946972
DOI: 10.1101/2024.06.19.24309184 -
Research Square Jun 2024Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by...
Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by stiff movement, muscle contractures, and abnormal gait that can diminish quality of life. Spastic CP accounts for approximately 83% of all CP cases and frequently co-occurs with other complex conditions, like epilepsy. An estimated 42% of spastic CP cases have co-occurring epilepsy. Unfortunately, CP is often difficult to diagnose. Although most children with CP are born with it or acquire it immediately after birth, many are not identified until after 19 months of age with CP diagnosis often not confirmed until 5 years of age. New bioinformatic approaches to identify CP earlier are needed. Recent studies indicate that altered DNA methylation patterns associated with CP may have diagnostic value. The potential confounding effects of co-occurrent epilepsy on these patterns are not known. We evaluated machine learning classification of CP patients with or without co-occurring epilepsy. Whole blood samples were collected from 30 study participants diagnosed with epilepsy (n=4), spastic CP (n=10), both (n=8), or neither (n=8). A novel Support-Vector-Machine learning algorithm was developed to identify methylation loci that have ability to classify CP from controls in the presence or absence of epilepsy. This algorithm was also employed to measure classification ability of identified methylation loci. After preprocessing of data, isolation of important methylation loci was performed in a binary comparison between CP and controls, as well as in a 4-way scheme, encapsulating epilepsy diagnoses. The classification ability was similarly assessed. CP Classification performance wasevaluated with and without inclusion of epilepsy as a feature. Median F1 scoreswere 0.67 in 4-class comparison, and 1.0 in the binary classification, outperforming Linear-Discriminant-Analysis (0.57 and 0.86, respectively). This novel algorithm was able to classify study participants with spastic CPand/or epilepsy from controls with significant performance. The algorithm shows promise for rapid identification in methylation data of diagnostic methylation loci. In this model, Support Vector Machines outperformed Linear Discriminant Analysis in classification. In the evaluation of epigenetics-based diagnostics for CP, epilepsy may not be a significant confounding factor.
PubMed: 38946953
DOI: 10.21203/rs.3.rs-4560364/v1 -
Journal of Cellular Physiology Jun 2024Schwannomas are benign tumors of the peripheral nervous system arising from the transformation of Schwann cells (SCs). On the whole, these tumors are related to...
Schwannomas are benign tumors of the peripheral nervous system arising from the transformation of Schwann cells (SCs). On the whole, these tumors are related to alterations of the neurofibromin type 2 gene, coding for the oncosuppressor merlin, a cytoskeleton-associated protein belonging to the ezrin-radixin-moesin family. However, the underlying mechanisms of schwannoma onset and progression are not fully elucidated, whereas one of the challenges might be the environment. In this light, the exposure to electromagnetic field (EMF), generated by the use of common electrical devices, has been defiantly suggested as the cause of SCs transformation even if the evidence was mostly epidemiologic. Indeed, insubstantial mechanisms have been so far identified to explain SCs oncotransformation. Recently, some in vitro evidence pointed out alterations in proliferation and migration abilities in SCs exposed to EMF (0.1 T, 50 Hz, 10 min). Here, we used the same experimental paradigma to discuss the involvement of putative epigenetic mechanisms in SCs adaptation to EMF and to explain the occurrence of hypoxic alterations after the exposure. Our findings indicate a set of environmental-induced changes in SCs, toward a less-physiological state, which may be pathologically relevant for the SCs differentiation and the schwannoma development.
PubMed: 38946084
DOI: 10.1002/jcp.31365