To investigate the impact of the preoperative systemic inflammatory index CALLY (albumin × lymphocyte count / C-reactive protein) and intraoperative preservation of the LCAon postoperative complications and the occurrence of low anterior resection syndrome (LARS) following robot-assisted radical surgery for mid–low rectal cancer. Additionally, to develop a Logistic regression–based nomogram prediction model for postoperative LARS and evaluate its clinical utility. In this retrospective study, a total of 118 patients who underwent robot-assisted total mesorectal excision (TME) for mid–low rectal cancer at Shanxi Bethune Hospital between January 2021 and December 2024 were included. LARS was defined as the primary outcome and assessed at 6 months postoperatively using a validated LARS scoring questionnaire. Minor to Major LARS (LARS score > 20) was defined as a binary outcome variable. Postoperative complications were considered secondary outcomes and were recorded within 30 days after surgery for descriptive analysis. Least absolute shrinkage and selection operator (LASSO) regression was applied to identify candidate predictors, which were subsequently incorporated into univariate and multivariate Logistic regression analyses to construct a predictive model and corresponding nomogram for LARS. Internal validation was performed using the Bootstrap resampling method, and model performance was evaluated in terms of discrimination, calibration, and clinical net benefit. Among the 118 patients, 32 (27.12

Background: The malignant progression of lung adenocarcinoma (LUAD) is not only a hallmark of this prevalent cancer but is also closely linked to epigenetic regulation, particularly N6-methyladenosine (m6A) methylation. Disruption of the m6A regulatory machinery results in the uncontrolled upregulation of multiple oncogenic drivers, thereby fueling tumor development. Our study investigated the mechanism by which G Protein Subunit Gamma 4 (GNG4), a gene upregulated via m6A modification, promoted LUAD by enhancing its mRNA stability and subsequently inhibiting the cGAS-STING pathway. This provides novel mechanistic insight for clinical LUAD research. Methods: Based on transcriptomic and m6A sequencing data from The Cancer Genome Atlas Program (TCGA) database, the candidate gene GNG4, associated with m6A regulation, was identified. Correlations of GNG4 expression with two m6A regulators-the writer Vir Like M6A Methyltransferase Associated (VIRMA) and reader Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3)-were statistically evaluated. Prediction of the biological functions pertaining to GNG4 was performed using Single-gene Gene Set Enrichment Analysis (Single-gene GSEA). Cellular experiments, including gene knockdown/overexpression, Western blot, flow cytometry, m6A-related assays, and cellular senescence detection, as well as animal models were employed to investigate the regulatory effects of m6A-modified GNG4 on the cGAS-STING pathway and its impact on cell cycle progression and cellular senescence. Results: TCGA data combined with functional experiments demonstrated that GNG4 was highly expressed in LUAD (p < 0.05). Knockdown of GNG4 activated the cGAS-STING pathway, upregulated p21, induced G1/S cell cycle arrest (p <0.05) and cellular senescence (p < 0.05), thereby inhibiting LUAD cell proliferation (p < 0.05) and tumor growth (p < 0.05). Mechanistically, increased GNG4 mRNA expression was associated with elevated m6A modification in LUAD. GNG4 expression was positively correlated with the m6A writer VIRMA and the m6A reader IGF2BP3. Knockdown of VIRMA or IGF2BP3 significantly reduced both m6A modification and mRNA expression of GNG4 (p < 0.05), thereby alleviating its suppressive effect on the cGAS-STING pathway, promoting cellular senescence (p < 0.05), and inhibiting proliferation in LUAD cells (p < 0.05). Conclusion: The upregulation of m6A modification of GNG4 in LUAD enhances its mRNA stability, which in turn suppresses the cGAS-STING signaling pathway, ultimately inhibiting cellular senescence and promoting LUAD cell proliferation, thereby driving disease progression.

Early, non-invasive identification can generally enhance the survival rate for asymptomatic pancreatic cancer (PC). This systematic review and meta-analysis is conducted to evaluate the precision of diagnosing PC using serum and duodenal fluid exosomes. Following the guidelines of PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses), searches were conducted in the PubMed, Embase, Cochrane Library, and Web of Science databases in April 2024. A study was considered appropriate if it provided diagnostic precision and accuracy for patients with pancreatic cancer. The combined diagnostic impact was assessed by calculating the area beneath the aggregated SROC curve, and the quality of the studies included was evaluated using the QUADAS-2 checklist. All statistical evaluations and graphical representations utilized STATA 14.0. Employing the terms “exosomes” and “pancreatic cancer” along with the search methodology, research was conducted across PubMed, Web of Science, Cochrane, and Embase databases. A total of 1202 studies were extracted from the databases, out of which nine were ultimately selected based on specific inclusion and exclusion standards. Across eight studies, exosomes were isolated from serum, while in a different one, they were taken from duodenal fluid. This document conducts subgroup analyses focusing on various types of exosome biomarkers, their origins, isolation techniques, and methods for analyzing biomarkers. Within the subset of exosome biomarker types, the group with exosomal cell surface proteoglycan exhibited the greatest combined sensitivity (0.96 (95

Lung squamous-cell carcinoma (LUSC) is a highly aggressive malignancy with a poor prognosis. Tertiary lymphoid structures (TLS) play a crucial role in the immune response and significantly influence the efficacy of immunotherapy. However, the prognostic and immunological implications of TLS-associated molecular subtypes in LUSC remain unclear. In this study, we applied 10 multi-omics integration strategies to perform a multi-omics analysis of the mRNA expression profiles, DNA methylation, and genomic mutation data of 39 TLSs-related genes, along with long non-coding RNA (lncRNA) expression profiles, to generate integrated consensus subtypes of LUSC. Four molecular subtypes were identified: cancer subtype 1 (CS1), CS2, CS3, and CS4. We observed a significant difference in overall survival between cancer subtype 1 (CS1) and CS3. Subsequently, we identified 33 prognosis-related genes based on differential expression between CS1 and CS3, which were further refined to 20 genes using the least absolute shrinkage and selection operator (LASSO) regression algorithm, and constructed a prognostic signature termed the LUSC-Survival Prediction Index (LUSCSPI). The high-LUSCSPI group demonstrated a poor prognosis and was more likely to benefit from treatment with nine chemotherapeutic agents (shikonin, doxorubicin, CMK, S-Trityl-L-cysteine, paclitaxel, DMOG, gemcitabine, erlotinib, and crizotinib). In contrast, the low-LUSCSPI group exhibited a more favorable prognosis, with thapsigargin and cisplatin identified as promising treatment options. In conclusion, our results highlight the potential of LUSCSPI as an independent prognostic factor for LUSC. Further, the multi-omics consensus approach provides a robust foundation for prognostic stratification in LUSC patients, facilitating personalized treatment and disease management.

Heat shock has been known to induce hyperplasia in esophageal epithelial cells. It is widely considered as a crucial risk factor in the initiation and development of esophageal squamous cell carcinoma (ESCC), yet our understanding of the underlying mechanisms remains limited. The m6A modification of mRNA plays a role in mediating several cellular processes and is critical during cell stress. Our study revealed that inhibiting of m6A 'writer' components of ESCC cells exhibit higher death rates and slower recovery after heat shock. After normalization using mRNA expression profiles, 91.08 % of significantly changed m6A modifications aligned with corresponding mRNA abundance changes, with no evidence of over-modification, while the increase in m6A modification of 8.92 % of heat-shock associated genes far exceeded the increase in mRNA (hyper - m6A modification), and A/U rich motifs were commonly observed in the 3'UTR of these gene. Inside the nucleus, the binding of HSP70s in m6A writer complex promote the hyper - m6A modification in specific mRNAs after heat shock. The stronger nuclear localization of HSP70 in ESCC tissues correlates with a poor prognosis for the patients. In conclusion, our research revealed that the nuclear HSP70 protein could bind to the METTL3/14 writer complex and regulate mRNA's m6A modification. Our results provide a new perspective for research into how HSP70 protein regulates mRNA stability and suggests a new direction for the comprehensive prevention and treatment of ESCC.

AbstractBackgroundThis study aimed to evaluate the global burden of lung cancer due to ambient particulate matter (PM) pollution in women of childbearing age from 1990 to 2021.MethodsThis was a secondary analysis utilizing data from the Global Burden of Disease (GBD) 2021, with a focus on the temporal trends of the lung cancer burden attributable to ambient PM2.5 among women of childbearing age.ResultsIn 2021, the global mortality and disability‐adjusted life years (DALYs) number of lung cancer burden attributable to ambient PM2.5 among women of childbearing age were approximately 5205 and 247,211, respectively. The rate of lung cancer attributable to ambient PM2.5 among women of childbearing age increased between 1990 and 2021, with the age‐standardized mortality rate (ASMR) increasing from 0.22 (95% uncertainty interval [UI]; 0.13 to 0.33) to 0.25 (95% UI; 0.14 to 0.37; average annual percent change [AAPC] = 0.40) and the age‐standardized DALYs rate (ASDR) increasing from 10.39 (95% UI; 5.96 to 15.72) to 12.06 (95% UI; 6.83 to 17.51; AAPC = 0.41). The middle sociodemographic index (SDI) region, East Asia, and China had the heaviest burden, while the high SDI region showed the highest decrease. ASMR and ASDR exhibited an inverted U‐shaped relationship with the SDI.ConclusionsFrom 1990 to 2021, the lung cancer burden attributable to ambient PM2.5 among women of childbearing age exhibited an increasing trend. Furthermore, increasing attention should be paid to the middle SDI region, East Asia, and China, as ambient PM pollution remains a critical target for intervention.

IntroductionThis study aims to explore Programmed Death Receptor-1 (PD-1) and Programmed Death Ligand-1 (PD-L1) variations in Lung Cancer (LC) tissues and Peripheral Blood (PPB) and their association with immunotherapy efficacy and prognosis.Method72 patients with LC were included in the LC group and 39 patients with concurrent benign lung disease were included in the benign group. PD-1/PDL-1 was compared in PPB and lung tissue. All LC patients were treated with immunotherapy. The relationship between PD-1/PDL-1 in LC tissue and PPB and immunotherapy efficacy was analyzed. Patients were divided into death and survival groups, and PD-1/PDL-1 in tumor tissues and PPB were compared.ResultsThe authors found that PD-1 and PDL-1 positive expression in lung tissue and PPB in LC patients was elevated. Combined detection of PD-1 and PDL-1 was effective in diagnosing LC and evaluating the prognosis of LC patients. PD-1 and PDL-1 positive expression was reduced after disease remission while elevated in dead patients. The 3-year survival rate of patients with PD-1 positive expression was 45.45 % (25/55), which was lower (82.35 %, 14/17) than those with PD-1 negative expression. The 3-year survival rate of patients with positive and negative expression of PDL-1 was 48.78 % (20/41) and 61.29 % (19/31), respectively.DiscussionThe present results demonstrated that PD-1 and PDL-1 are abnormal in cancer tissue and PPB of LC patients. The combined detection of PD-1 and PDL-1 has diagnostic value for LC and evaluation value for the efficacy and prognosis of immunotherapy.

PURPOSE:The relationship between the levels of Systemic Immune-inflammation Index (SII) and chronic obstructive pulmonary disease (COPD), lung function, and COPD severity were not fully understood. We conducted this cross-sectional, population-based study to investigate the complex association between SII and COPD, lung function, and COPD severity among the US adults.METHODS:Overall, 18,349 participants were included in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018. The exposure variable was SII, calculated from platelet counts, neutrophil counts, and lymphocyte counts. Weighted univariable and multivariable logistic regression, subgroup analysis, and restricted cubic spline (RCS) regression were performed to assess the relationship between COPD, lung function, COPD severity and SII. Last, we used a propensity score matching (PSM) analysis to reduce selective bias and validate these relationships.RESULTS:Approximately 1,094 (5.96%) of the participants were diagnosed as COPD. The multivariable-adjusted odds ratio (OR) (95% confidence interval, CI) for the Q2 group (Log-SII > 2.740) was 1.39 (1.16 to 1.68). Before and after matching, multivariable logistic regression models revealed that increased Log-SII levels (SII Logarithmic transformation) associated positively with the risk of COPD. The subgroup analysis showed no interaction between Log-SII and a variety of variables (P for interaction > 0.05). RCS showed a reversed L-shaped relationship between Log-SII with COPD (P for nonlinear = 0.001) in individuals. In addition, we observed negative significant correlations between forced expiratory volume in one second (FEV1) / forced vital capacity (FVC) %, FEV1/FVC% predicted and SII, and reversed U-shaped curve relationships between FEV1, FEV1% predicted and SII. High SII level is associated with severity of COPD, especially at Global Initiative on Obstructive Lung Disease (GOLD) 1 and GOLD 3.CONCLUSIONS:In summary, the Log-SII level is associated with COPD risk, lung function, and COPD severity.

Background:Pancreatic cancer is a highly aggressive malignancy with poor prognosis, and there is an urgent need to understand its molecular mechanisms for early diagnosis and treatment. Despite surgical resection being the only effective treatment, most patients are diagnosed at an advanced stage, missing the optimal window for therapy. Identifying novel biomarkers is crucial for prognostic assessment, treatment planning, and early intervention. Ephrin A4 (EFNA4), a member of the receptor tyrosine kinase family, is involved in vascular and epithelial development via regulation of cell migration and rejection. However, the role of EFNA4 in pancreatic cancer has not been reported. Therefore, our study aimed to clarify the role of EFNA4 in pancreatic cancer through bioinformatics analysis and vitro experiments. Methods:The expression of EFNA4 and its potential value as a diagnostic and prognostic biomarker in pancreatic cancer was analyzed using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) database. According to the expression level of EFNA4, patients were divided into high expression group and low expression group, and the correlation between overall survival (OS) and disease-free survival (DFS) with different expression levels of EFNA4 and clinical parameters were analyzed. Subsequently, reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was performed to detect EFNA4 expression. The proliferation, invasion, and cloning ability of the cells were detected via Cell Counting Kit 8 (CCK8), Transwell, and plate cloning assays, respectively. Results:EFNA4 is highly expressed in pancreatic cancer, and upregulation of EFNA4 is associated with poor prognosis. In this study, EFNA4 expression was correlated with T stage and TNM (tumor-node-metastasis) stage of pancreatic cancer, and the median survival time and progression-free survival (PFS) were worse in those with high EFNA4 expression (394 days) than in those with low expression (525 days) [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.00-2.16, P=0.047]. In addition, EFNA4 was also found to be involved in the regulation of signal pathways such as cell adhesion, cyclic AMP, insulin secretion, pancreatic secretion, and protein digestion and absorption. In vitro experiments demonstrated that EFNA4 knockdown significantly inhibited the proliferation, cloning ability, and invasiveness of the PANC-1 and SW1990 pancreatic cancer cell lines. Conclusions:The abnormal expression of EFNA4 in pancreatic cancer is associated with poor prognosis. Knockout of EFNA4 gene could significantly inhibit the proliferation and invasion of pancreatic cancer cells. Therefore, EFNA4 may be one of the molecular targets for poor prognosis of patients with pancreatic cancer.

Hepatocellular cancer is one of the most serious types of cancer in the world, with high incidence and mortality rates. Most HCC patients with long-term chemotherapy develop chemoresistance, leading to a poor prognosis. However, the underlying mechanism of circRNAs in HCC chemoresistance remains unclear. Our research found that circ_0072391(circ_HMGCS1) expression was significantly upregulated in cisplatin-resistant HCC cells. The silence of circ_HMGCS1 attenuated the cisplatin resistance in HCC. Results showed that circ_HMGCS1 regulated the expression of miR-338-5p via acting as microRNA sponges. Further study confirmed that miR-338-5p regulated the expression of IL-7. IL-7 could remodel the immune system by improving T-cell function and antagonising the immunosuppressive network. IL-7 is an ideal target used to enhance the function of the immune system. circ_HMGCS1 exerts its oncogenic function through the miR-338-5p/IL-7 pathway. Inhibition of circ_HMGCS1/miR-338-5p/IL-7 could effectively attenuate the chemoresistance of HCC. IL-7 might be a promising immunotherapy target for HCC cancer treatment.

Abstract Background Tracheal, bronchus, and lung cancer (TBL) is one of the main cancer health problems worldwide, but data on the burden and trends of early‐onset tracheal, bronchus, and lung cancer (EO‐TBL) are sparse. The aim of the present study was to provide the latest and the most comprehensive burden estimates of the EO‐TBL cancer from 1990 to 2019. Methods Overall, we used data from the Global Burden of Disease (GBD) study in EO‐TBL cancer from 1990 to 2019. Evaluation metrics included incidence, mortality, and disability‐adjusted life years (DALYs). The joinpoint regression model was used to analyze the temporal trends. Decomposition analysis was employed to analyze the driving factors for EO‐TBL cancer burden alterations. Bayesian age‐period‐cohort (BAPC) analysis was used to estimate trends in the next 20 years. Results The global age‐standardized incidence rate (ASIR), age‐standardized mortality rate (ASMR), and age‐standardized DALYs rate (ASDR) for EO‐TBL cancer decreased significantly from 3.95 (95% uncertainty interval [UI]: 3.70–4.24), 3.41 (95% UI: 3.19–3.67), 158.68 (95% UI: 148.04–170.92) in 1990 to 2.82 (95% UI: 2.54–3.09), 2.28 (95% UI: 2.07–2.49), 106.47 (95% UI: 96.83–116.51) in 2019 with average annual percent change (AAPC) of −1.14% (95% confidence interval [CI]: −1.32 to −0.95), −1.37% (95% CI: −1.55 to −1.18), and − 1.35% (95% CI: −1.54 to −1.15) separately. The high and high‐middle sociodemographic index (SDI) region had a higher burden of EO‐TBL cancer but demonstrated a downward trend. The most prominent and significant upward trends were Southeast and South Asia, Africa, and women in the low SDI and low‐middle SDI quintiles. At the regional and national level, there were significant positive correlations between ASDR, ASIR, ASMR, and SDI. Decomposition analysis showed that population growth and aging have driven the increase in the number of incidence, mortality, and DALYs in the global population, especially among the middle SDI quintile and the East Asia region. The BAPC results showed that ASDR, ASIR, and ASMR in women would increase but the male population remained relatively flat over the next 20 years. Conclusions Although global efforts have been the most successful and effective in reducing the burden of EO‐TBL cancer over the past three decades, there was strong regional and gender heterogeneity. EO‐TBL cancer need more medical attention in the lower SDI quintiles and in the female population.

BACKGROUND:With increasing mortality and incidence, hepatocellular carcinoma (HCC) has become a major public health problem. The early diagnosis of HCC can improve its prognosis. The aim of this study was to identify potential risk factors related to HCC development and to establish a high-risk population rating scale. METHODS:A total of 853 patients with chronic hepatitis B (CHB) were enrolled in this study, including 403 patients with HCC as the case group and others as the control group. Their demographic and clinical characteristics were compared and the independent risk factors for HCC were assessed. Then, the optimal cutoff levels of these factors were analyzed by the receiver operating characteristic (ROC) method. A high-risk population rating scale was constructed based on the factors and then evaluated in the modeling population. RESULTS:The factors that presented statistically significant differences between the two groups included age, smoking, alcohol abuse, body mass index, triglyceride, high‒density lipoprotein cholesterol, aspartate transaminase, alanine transaminase, fasting plasma glucose, creatinine and uric acid. The ROC curve showed that the cutoff score for the HCC high risk population was 5 (AUC=0.74, P<0.001) and the Hosmer‒Lemeshow analysis showed that the fitting effect of this rating scale was good (P = 0.294). CONCLUSIONS:The integration of these factors can contribute to a prognostic score for the risk of HCC development, which offered certain clinical practicability.

Abstract Introduction Pulmonary nodules (PN) are a common finding in computed tomography (CT) images of the chest, and are identified in millions of patients each year in the United States. Accurate diagnosis of PN is crucial for early detection of cancer and proper treatment. This study aimed to investigate the applicability of machine learning (ML) algorithms in predicting malignant PN. Methods A total of 130 patients who underwent tumor resection and were pathologically diagnosed with PN were included in this study. Random Forest (RF), Support Vector Machine (SVM), Classification and Regression Tree (CART), and eXtreme Gradient Boosting (XGBoost) algorithms were employed to predict malignant PN outcomes. The most important features for malignant PN were identified using the RF, CART, and XGBoost algorithms. Results 80 patients were included in the final analysis, with 62.5% of nodules being malignant and 37.5% being benign. The four algorithms RF, SVM, CART and XGBoost all show great performance, with the AUC reaching 0.97, 0.92, 0.91, and 0.98, respectively. Additionally, the RF algorithm performed the best, with an accuracy of 0.9583, specificity of 0.8889, sensitivity of 1.0000, Kappa of 0.9091, positive predictive value (PPV) of 0.9375, and negative predictive value (NPV) of 1.0000. Besides, age, size, and density were identified as the most important features for predicting malignant PN. Conclusion ML algorithms can provide accurate prediction of malignant PN, which could help establish an early auxiliary diagnosis model. This model could facilitate early detection, diagnosis, and treatment of PN, potentially improving the quality of life and reducing mortality rates. However, further studies with larger sample sizes are needed to confirm the findings of this study.

Background Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disorder defined by xerostomia and keratoconjunctivitis sicca, and its etiology remains unknown. N6-methyladenosine (m 6 A) is the predominant posttranscriptional modification in eukaryotic mRNAs and is dynamically regulated by m 6 A regulators. Dysregulation of m 6 A modification is closely associated with several autoimmune disorders, but the role of m 6 A modification in pSS remains unknown. This study investigated the potential role of m 6 A and m 6 A-related regulators in pSS patients with dry eye. Methods This cross-sectional study included forty-eight pSS patients with dry eye and forty healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) were isolated, and the level of m 6 A in total RNA was measured. The expression of m 6 A regulators was determined utilizing real-time PCR and western blotting. The serological indicators detected included autoantibodies, immunoglobulins (Igs), complement factors (Cs), and inflammatory indicators. Dry eye symptoms and signs were measured, including the ocular surface disease index, Schirmer’s test (ST), corneal fluorescein staining score (CFS), and tear break-up time. Spearman’s correlation coefficient was employed to assess the associations of m 6 A and m 6 A-related regulator expression with clinical characteristics. Results The expression level of m 6 A was markedly increased in the PBMCs of pSS patients with dry eye compared to HCs (P value <0.001). The relative mRNA and protein expression levels of the m 6 A regulators methyltransferase-like 3 (METTL3) and YT521-B homology domains 1 were markedly elevated in pSS patients with dry eye (both P value <0.01). The m 6 A RNA level was found to be positively related to METTL3 expression in pSS patients (r = 0.793, P value <0.001). Both the m 6 A RNA level and METTL3 mRNA expression correlated with the anti-SSB antibody, IgG, ST, and CFS (all P values < 0.05). The m 6 A RNA level was associated with C4 (r = -0.432, P value = 0.002), while METTL3 mRNA expression was associated with C3 (r = -0.313, P value = 0.030). Conclusions Our work revealed that the upregulation of m 6 A and METTL3 was associated with the performance of serological indicators and dry eye signs in pSS patients with dry eye. METTL3 may contribute to the pathogenesis of dry eye related to pSS.

Hepatocellular carcinoma (HCC) is a major global public health concern, with approximately 79 million new cases and 75 million HCC-related deaths occurring annually worldwide. Among the drugs, cisplatin (DDP) is considered a cornerstone and has been shown to significantly inhibit cancer progression. However, the mechanism underlying DDP-resistance in HCC remains unclear. This study aimed to identify a novel lncRNA. FAM13A Antisense RNA 1 (FAM13A-AS1), that promotes the proliferation of DDP-resistant HCC cells and to elucidate its downstream and upstream mechanisms in the progression of HCC DDP-resistance. Our results suggest that FAM13A-AS1 interacts directly with Peroxisome Proliferator Activated Receptor γ (PPARγ), stabilizing its protein through de-ubiquitination. Moreover, our findings indicate that Paired Like Homeobox 2B (PHOX2B) transcriptionally regulates the expression of FAM13A-AS1 in HCC cells. These results shed new light on the understanding of the progression of HCC DDP-resistance.

miR-126 is involved in lung cancer progression. This study explored effects of miR-126 with arsenic trioxide nanoparticles as a carrier on lung cancer cell invasion and metastasis, and possible molecular mechanisms. Four groups, including blank group, positive control group, miR-126 group, and epidermal growth factor receptor (EGFR)/protein kinase B (AKT)/Mammalian target of rapamycin (mTOR) (EGFR/AKT/mTOR) signal pathway activation group (agonist group) were set. Positive control group was treated with anticancer drug paclitaxel. Cells in miR-126 group were transfected with nanoparticle-encapsulated miR-126, while cells in the agonist group were treated with EGFR/AKT/mTOR signal pathway agonist. Cell metastasis, invasion, EGFR/AKT/mTOR signaling pathway activity, expressions of N-cadherin, Vimentin, MMP-9, MMP-2, SOX4, EGFR, and AKT and mTOR were measured, and relationship between miR-126 and SOX4 was investigated. Agonist treatment significantly increased metastasis, while miR-126 transfection significantly decreased cell invasion and metastasis (P < 0.05). Compared to blank and agonist group, the expressions of N-cadherin, Vimentin, MMP-9, MMP-2, SOX4, EGFR, AKT, and mTOR were down-regulated in miR-126 group and PC group (P < 0.05). In contrast, E-cadherin was up-regulated (P < 0.05). miR-126 was bound to 3′UTR of SOX4. Moreover, the miR-126 decreased SOX4 protein, thereby inhibiting the EGFR signaling pathway, suppressing EGFR to further inhibit AKT and mTOR expression, and finally inhibiting lung cancer progression. Its molecular mechanism is mainly related to suppression of EGFR/AKT/mTOR signaling.

Mounting evidences have indicated that RNA N-6-methyladenosine (m(6)A) modification played important roles in tumor formation and growth. However, it is rarely reported that m(6)A modifications are involved in the immune regulation and tumor microenvironment (TME) formation. In this study, we aimed to investigate the correlation between m(6)A modifications and TME regulation of colon adenocarcinoma (COAD) by bioinformatic analysis. NMF algorithm was applied to carry out consensus molecular subtype analysis on 36 selected m(6)A regulators regarding methylation modification, to identify m(6)A modification patterns and characteristics of m(6)A related genes in colon adenocarcinoma (COAD). Further, the relative infiltration levels of different immune cell subsets were quantified by ssGSEA and CIBERSORT algorithms, and a m(6)Sig scoring scheme was constructed to predict the prognosis and evaluate the response to immunotherapy in the patients with COAD. Among 579 COAD samples, we identified three different m(6)A modification patterns which were related to different biological pathways and clinical outcomes. Then, a scoring scheme termed "m(6)Sig score" was developed based on m(6)A-related characteristic genes, and was utilized to score patients with COAD into groups. We found that COAD patients with lower m(6)Sig scores exhibited prolonged survival and potentiated immune infiltration, which were associated with higher tumor mutation load, lower PD-L1 expression, and higher mutation rates of SMG (such as TTN and KRAS). Moreover, analysis regarding evaluation of immune response revealed that the patients with lower m(6)Sig scores had higher Immunophenoscore. Collectively, our study provided in depth insight into the interactions between m(6)A modification and regulation of TME. In addition, the quantitative evaluation of m(6)A modification patterns in our results may have implications in further immunotherapy for individual COAD patients.

Colorectal cancer (CRC) is the third cause of cancer-related death and the fourth most frequently diagnosed cancer across the globe. The objective of this study is to obtain novel and effective diagnostic markers to enrich CRC diagnosis methods. Herein, exosomal miRNA expression data of CRC and normal blood were subjected to XGBoost algorithm, and 5 miRNAs related to CRC diagnosis were primarily confirmed. Then multilayer perceptron (MLP) classifiers were constructed based on different subsets. Via integrated feature selection (IFS), we noticed that the MLP classifier constructed by the first four miRNAs (miR-654-5p, miR-126, miR-10b, and miR-144) had the highest Matthews correlation coefficient (MCC). Subsequently, principal component analysis (PCA) for dimensionality reduction was performed on samples based on the miR-654-5p, miR-126, miR-10b, and miR-144 expression data. The signature based on these four feature miRNAs, as the analysis indicated, could effectively distinguish CRC samples from normal samples. Further, we extracted the exosomes from clinical blood samples and applied qRT-PCR analysis, which revealed that the expression of these four feature miRNAs was in the trend of that in the test set. Collectively, these four feature miRNAs might be tumor biomarkers in the serum, and our study offers innovative thinking on early-stage CRC diagnosis.

DNA topoisomerase II alpha (TOP2A) reportedly plays a crucial role in several cancers, however, the precise regulatory role of TOP2A in metastatic characteristics of glioma is still poorly understood. Herein, we sought to elucidate the mechanisms by which TOP2A affects the metastatic phenotypes of glioma. We observed that a high level of TOP2A expression was dramatically linked with inferior survival in glioma patients while silencing of TOP2A impaired glioma cell proliferation and aggressiveness. TOP2A was found to directly interact with β-catenin and facilitated its translocation into the nucleus. Mechanistically, TOP2A effectively induced glioma cell growth and invasion in a β-catenin-dependent manner. Overall, we pinpoint TOP2A as a critical activator of the Wnt/β-catenin pathway in glioma, promoting cell growth, migration, and invasion.

Objective To clarify the modulatory mechanism of miR-31-5p in lung adenocarcinoma (LUAD) progression in vivo and in vitro. Methods The Cancer Genome Atlas (TCGA) database was employed to access LUAD-related miRNA and mRNA expression data. Downstream targets of miR-31-5p were predicted by public databases. The interaction between miR-31-5p and TNS1 was determined by dual-luciferase reporter assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to measure miR-31-5p and TNS1 expression levels in LUAD cells. Western blot was introduced to test protein expression levels of TNS1, p53, and apoptosis-related proteins. In-vitro functional assays were conducted to evaluate the biological effects of miR-31-5p on cell proliferation, colony formation, migration, and apoptosis. In-vivo tumor xenograft experiment was applied to examine the effects of miR-31-5p on LUAD tumor growth, followed by immunochemistry assays for assessing TNS1 and p53 expression levels in the tumor tissue. Results miR-31-5p was prominently upregulated in LUAD tissue and was identified to present a similar trend in LUAD cell lines H1299, H23, and A549. miR-31-5p overexpression exerted an active role in cell proliferation and migration, but it suppressed cell apoptosis. Additionally, a reverse correlation between miR-31-5p and TNS1 regarding the expression level was identified, and TNS1 was verified to be a direct target of miR-31-5p . Besides, it was further validated by the rescue experiments that the tumor-promoting effects of miR-31-5p on LUAD cell functions were attenuated by TNS1 overexpression to some extent. The results based on the tumor xenograft experiment revealed that LUAD cell growth could be facilitated by miR-31-5p via the TNS1 / p53 axis. Conclusion miR-31-5p facilitates LUAD cell progression mediated by the TNS1 / p53 axis.