MAFF confers vulnerability to cisplatin-based and ionizing radiation treatments by modulating ferroptosis and cell cycle progression in lung adenocarcinoma.

AIMS: Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD. METHODS: CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models. RESULTS: Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments. CONCLUSIONS: MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients.

Deconvoluting Surface and Bulk Charge Storage Processes in Redox-Active Oxides by Integrating Electrochemical and Optical Insights.

Redox-active transition metal oxides (TMOs) play crucial roles in diverse energy storage and conversion technologies, such as batteries and pseudocapacitors. These materials show intricate electrochemical charge storage processes, encompassing both bulk ion-intercalation, typical of battery electrodes, and pseudocapacitive-like behavior localized near the surfaces. However, understanding the underlying mechanisms of charge storage in redox-active TMOs is challenging due to the coexistence of these behaviors. In this study, we propose an integrated approach that combines operando electrochemical and optical techniques to disentangle the contributions of bulk and surface phenomena. Using birnessite δ-MnO2-x as a model system, we account for surface pseudocapacitive-like layers and employ a refined model that incorporates both surface reactions and bulk chemical diffusion. This methodology allows us to extract essential kinetic parameters, establishing a fundamental framework for unraveling surface and bulk electrochemical processes. This advancement provides a valuable tool for the rational design of energy storage devices, enhancing our ability to tailor these materials for specific applications.

Unraveling the causality between gastroesophageal reflux disease and increased cancer risk: evidence from the UK Biobank and GWAS consortia.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. METHODS: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. RESULTS: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. CONCLUSIONS: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.

The associations between dysregulation of human blood metabolites and lung cancer risk: evidence from genetic data.

BACKGROUND: Metabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear. METHODS: Genomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings. RESULTS: A total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer. CONCLUSION: This study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Strong Electron Transfer in Covalently Integrating Cu(I)-Organic Frameworks Enabling Effective Radionuclide Capture.

Rational construction of strong electron-transfer materials remains a challenging task. Herein, we show a design rule for the construction of strong electron-transfer materials through covalently integrating electron-donoring Cu(I) clusters and electron-withdrawing triazine monomers together. As expected, Cu-CTF-1 (Cu(I)-triazine framework) was found to enable strong electron transfer up to 0.46|e| from each Cu(I) metal center to each adjacent triazine fragment. This finally leads to good spatial separation in both photogenerated electron-hole pairs and function units for photocatalytic uranium reduction under ambience and no sacrificial agent and to good charge separation of [I+][I5-] for I2 immobilization under extremely rigorous conditions. The results have not only opened up a structural design principle to access electron-transfer materials but also solved several challenging tasks in the field of radionuclide capture and CTFs.

The forkhead box O3 (FOXO3): a key player in the regulation of ischemia and reperfusion injury.

Forkhead box O3 is a protein encoded by the FOXO3 gene expressed throughout the body. FOXO3 could play a crucial role in longevity and many other pathologies, such as Alzheimer's disease, glioblastoma, and stroke. This study is a comprehensive review of the expression of FOXO3 under ischemia and reperfusion (IR) and the molecular mechanisms of its regulation and function. We found that the expression level of FOXO3 under ischemia and IR is tissue-specific. Specifically, the expression level of FOXO3 is increased in the lung and intestinal epithelial cells after IR. However, FOXO3 is downregulated in the kidney after IR and in the skeletal muscles following ischemia. Interestingly, both increased and decreased FOXO3 expression have been reported in the brain, liver, and heart following IR. Nevertheless, these contribute to stimulating ischemia and reperfusion injury via the induction of inflammatory response, apoptosis, autophagy, mitophagy, pyroptosis, and oxidative damage. These results suggest that FOXO3 could play protective effects in some organs and detrimental effects in others against IR injury. Most importantly, these findings indicate that controlling FOXO3 expression, genetically or pharmacologically, could contribute to preventing or treating ischemia and reperfusion damage.

Deficiency of interleukin-36 receptor antagonist (DITRA): An analysis of 58 Chinese patients in a tertiary hospital in Taiwan.

DITRA, acronym for deficiency of interleukin-36 receptor antagonist (IL36RN), leads to unopposed pro-inflammatory signalling which typically manifests as pustular psoriasis. In Asian patients, c.115 + 6 T > C mutation is the most common and important single-nucleotide variant in DITRA. We present the largest case series consisting of 58 DITRA patients carrying heterozygous or homozygous c.115 + 6 T > C mutation. The mean age of onset (±SD) was 20.74 (±20.86), and the median age of onset was 13 years old. Twelve patients (20.7%) had disease onset before the age of two. Twenty-two patients (37.9%) had disease onset between the ages of 2-18. Main clinical phenotype was generalized pustular psoriasis (GPP) with systemic symptoms (33 patients, 56.9%), followed by acrodermatitis continua of Hallopeau (ACH) (16 patients, 27.6%). Nearly half of our patients (27 patients, 46.6%) ever had ACH, and only three of them are free of ACH currently, which indicates that the development of ACH is relatively persistent and irreversible. Thirty-four patients (58.6%) had recurrent GPP and 29 patients (50%) have been admitted due to GPP flare. Compared to those with heterozygous (C/T) mutation, more patients carrying homozygous mutation (C/C) have recurrent episodes of GPP (C/T vs. C/C: 25.53 vs. 76.47%, p = 0.0367). Two patients with squamous cell carcinomas arising from the pustular psoriasis skin lesions were noted. Two patients had elevated serum IgG4 levels.

Ultrahigh Oxygen Ion Mobility in Ferroelectric Hafnia.

Ferroelectrics and ionic conductors are important functional materials, each supporting a plethora of applications in information and energy technology. The underlying physics governing their functional properties is ionic motion, and yet studies of ferroelectrics and ionic conductors are often considered separate fields. Based on first-principles calculations and deep-learning-assisted large-scale molecular dynamics simulations, we report ferroelectric-switching-promoted oxygen ion transport in HfO_{2}, a wide-band-gap insulator with both ferroelectricity and ionic conductivity. Applying a unidirectional bias can activate multiple switching pathways in ferroelectric HfO_{2}, leading to polar-antipolar phase cycling that appears to contradict classical electrodynamics. This apparent conflict is resolved by the geometric-quantum-phase nature of electric polarization that carries no definite direction. Our molecular dynamics simulations demonstrate bias-driven successive ferroelectric transitions facilitate ultrahigh oxygen ion mobility at moderate temperatures, highlighting the potential of combining ferroelectricity and ionic conductivity for the development of advanced materials and technologies.

Optimization of limonin invertase production by scaling up Aspergillus tubingensis UA13 fermentation to a 5-l scale.

The enzymatic approach is a highly effective and the major scientific method to eliminating bitter components in citrus-derived products nowadays. Microbial production of limonin invertase stands out due to its pivotal role in the removal of the bitter substance, limonin. The optimization of fermentation parameters and the study of scale-up fermentation are imperative for product commercialization. In this study, we focused on optimizing stirring speed, fermentation temperature, and initial pH to enhance the growth and limonin invertase production by the Aspergillus tabin strain UA13 in a 5-l stirred-tank bioreactor. Our results revealed the following optimal parameters are: a stirring speed of 300 rpm, a fermentation temperature of 35°C and a pH 5.0. Under these optimized conditions, the limonin invertase activity reached its peak at 63.38 U ml-1, representing a 1.67-fold increase compared to the unoptimized conditions (38.10 U ml-1), while also reducing the fermentation duration by 12 h. Furthermore, our research demonstrated that limonin invertase effectively hydrolyze limonin in grapefruit juice, reducing its content from 13.28 to 2.14 µg ml-1, as determined by HPLC, resulting in a 6.21-fold reduction of the bitter substance.

Comparison of joint awareness after total knee arthroplasty, medial unicompartmental knee arthroplasty, and high tibial osteotomy: a retrospective study.

INTRODUCTION: This study aimed to compare the Forgotten Joint Score-12(FJS) outcomes and the minimum clinically important difference (MCID) of the FJS after high tibial osteotomy (HTO), unicompartmental knee arthroplasty (UKA), and total knee arthroplasty (TKA) with short-term follow-up (at least 2 years). Another objective of the study is to investigate the factors influencing FJS. It is hypothesized that there are differences in FJS outcomes among the three procedures. METHODS: Patients who underwent HTO, UKA, and TKA from January 2016 to December 2020 and were followed up for a minimum of 2 years were included in the study. The FJS were analyses from a cohort of people who submitted data to two years. The preoperative and postoperative clinical outcomes were compared and evaluated the patient-related factor. The FJS scores were predicted using multiple linear regression analysis. Additionally, Patient's Joint Perception (PJP) questions were used as anchors to determine the achievement of the forgotten joint, and FJS MCID were calculated using the receiver operating characteristic curve (ROC). RESULTS: Three hundred eighty-nine patients were included in the final study, and there were 111 patients in HTO groups,128patients in UKA groups, and 150 patients in TKA groups. The mean follow-up was 47.0 months. There was a significant difference in the total FJS, between the HTO, UKA, and TKA groups (FJS:59.38 ± 7.25, 66.69 ± 7.44 and 56.90 ± 6.85, p < 0.001. We found the MCID of the FJS of HTO, UKA, and TKA were 63.54, 69.79, and 61.45, respectively. In multiple linear regression, younger age, and higher FS were significant predictors of better FJS. CONCLUSION: Medial UKA demonstrated lower patient awareness in comparison to HTO and TKA, as assessed by the FJS. Younger age and higher FS were identified as significant predictors of improved FJS, providing valuable guidance for surgical decision-making.

Finite element analysis of the mechanical strength of a new hip Spacer.

BACKGROUND AND OBJECTIVE: At present, the influence of the internal metallic endoskeleton of Spacer on the biomechanical strength of Spacer remains unclear. The aim of this study was to analyze the mechanical stability of a novel Spacer applying a annular skeleton that mimics the structure of trabecular bone using finite element methods. METHEDS: The femur models of three healthy individuals and skeletonless Spacer, K-Spacer, and AD-Spacer were assembled to create 15 3D models. Finite element analysis was performed in an Ansys Bench2022R1. Biomechanical parameters such as stress and strain of the Spacer, internal skeleton and femur were evaluated under three loads, which were applied with the maximum force borne by the hip joint (2100 N), standing on one leg (700 N), and standing on two legs (350 N). The mechanical properties of the new hip Spacer were evaluated. RESULT: The stresses on the medial and lateral surfaces of the AD-Spacer and K-Spacer were smaller than the stresses in the state without skeletal support. The maximum stresses on the medial and lateral surfaces of the AD-Spacer were smaller than those of the inserted K-Spacer, and the difference gradually increased with the increase of force intensity. When the skeleton diameter was increased from 3 to 4 mm, the stresses in the medial and lateral sides of the AD-Spacer and K-Spacer necks decreased. The stress of both skeletons was concentrated at the neck, but the stress of the annular skeleton was evenly distributed on the medial and lateral sides of the skeleton. The mean stress in the proximal femur was higher in femurs with K-Spacer than in femurs with AD-Spacer. CONCLUSIONS: AD-Spacer has lower stress and higher load-bearing capacity than K-Spacer, and the advantages of AD-Spacer are more obvious under the maximum load state of hip joint.

Metformin inhibits human non-small cell lung cancer by regulating AMPK-CEBPB-PDL1 signaling pathway.

Metformin has been found to have inhibitory effects on a variety of tumors. However, its effects on non-small cell lung cancer (NSCLC) remain unclear. We demonstrated that metformin could inhibit the proliferation of A549 and H1299 cells. RNA transcriptome sequencing revealed that PDL1 was significantly downregulated in both cell types following treatment with metformin (P < 0.001). Jaspar analysis and chromatin immunoprecipitation showed that CEBPB could directly bind the promoter region of PDL1. Western blotting showed that protein expression of the isoforms CEBPB-LAP*, CEBPB-LAP, and CEBPB-LIP was significantly upregulated and the LIP/LAP ratio was increased. Gene chip analysis showed that PDL1 was significantly upregulated in A549-CEBPB-LAP cells and significantly downregulated in A549-CEBPB-LIP cells (P < 0.05) compared with CEBPB-NC cells. Dual-luciferase reporter gene assay showed that CEBPB-LAP overexpression could promote transcription of PDL1 and CEBPB-LIP overexpression could inhibit the process. Functional assays showed that the changes in CEBPB isoforms affected the function of NSCLC cells. Western blotting showed that metformin could regulate the function of NSCLC cells via AMPK-CEBPB-PDL1 signaling. Animal experiments showed that tumor growth was significantly inhibited by metformin, and atezolizumab and metformin had a synergistic effect on tumor growth. A total of 1247 patients were retrospectively analyzed, including 166 and 1081 patients in metformin and control groups, respectively. The positive rate of PDL1 was lower than that of the control group (HR = 0.338, 95% CI = 0.235-0.487; P < 0.001). In conclusion, metformin inhibited the proliferation of NSCLC cells and played an anti-tumor role in an AMPK-CEBPB-PDL1 signaling-dependent manner.

Cisplatin resistance-related multi-omics differences and the establishment of machine learning models.

OBJECTIVES: Platinum-based chemotherapies are currently the first-line treatment of non-small cell lung cancer. This study will improve our understanding of the causes of resistance to cisplatin, especially in lung adenocarcinoma (LUAD) and provide a reference for therapeutic decisions in clinical practice. METHODS: Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA) and Zhongshan hospital affiliated to Fudan University (zs-cohort) were used to identify the multi-omics differences related to platinum chemotherapy. Cisplatin-resistant mRNA and miRNA models were constructed by Logistic regression, classification and regression tree and C4.5 decision tree classification algorithm with previous feature selection performed via least absolute shrinkage and selection operator (LASSO). qRT-PCR and western-blotting of A549 and H358 cells, as well as single-cell Seq data of tumor samples were applied to verify the tendency of certain genes. RESULTS: 661 cell lines were divided into three groups according to the IC50 value of cisplatin, and the top 1/3 (220) with a small IC50 value were defined as the sensitive group while the last 1/3 (220) were enrolled in the insensitive group. TP53 was the most common mutation in the insensitive group, in contrast to TTN in the sensitive group. 1348 mRNA, 80 miRNA, and 15 metabolites were differentially expressed between 2 groups (P < 0.05). According to the LASSO penalized logistic modeling, 6 of the 1348 mRNAs, FOXA2, BATF3, SIX1, HOXA1, ZBTB38, IRF5, were selected as the associated features with cisplatin resistance and for the contribution of predictive mRNA model (all of adjusted P-values < 0.001). Three of 6 (BATF3, IRF5, ZBTB38) genes were finally verified in cell level and patients in zs-cohort. CONCLUSIONS: Somatic mutations, mRNA expressions, miRNA expressions, metabolites and methylation were related to the resistance of cisplatin. The models we created could help in the prediction of the reaction and prognosis of patients given platinum-based chemotherapies.

Cystathionine beta-Synthase in hypoxia and ischemia/reperfusion: A current overview.

Besides its presence in the liver, brain, pancreas, and kidney, Cystathionine beta-Synthase (CBS) is also found in many other tissues, where it acts through regulation of hydrogen sulfide (H2S) generation and homocysteine (Hcy) metabolism, to interact with other molecules during hypoxia and ischemia/reperfusion (I/R). Despite all the advances accumulated in decades of research on CBS, there are still controversies, and the role of CBS in many tissues during hypoxia and I/R is still unclear. Herein, we overviewed the expression level, the role, and the mechanism through which CBS interacts with other molecules during hypoxia and I/R processes in tissues of humans and other organisms. CBS appeared to be deregulated under hypoxia and I/R, after which it mostly conduces the reparation in the concerned tissue after damage; however, it has been described that CBS could also play pathological effects (exacerbating the damage). From all findings, it emerges that variations in CBS expression in these conditions depend on the organism, tissue, or subcellular localization, CBS could play both protective and pathological effects; and artificially controlling CBS expression may help to provide novel strategies for treatment or prevention of hypoxia and I/R -related injury.

Multi-step Phase Transformation from Metal-Organic Frameworks to Inorganic Compounds for High-Purity Th(IV) Generation.

The generation of high-purity thorium is the precondition for next-generation nuclear energy; however, this remains a challenging task. To this end, we present herein an ultrasimple technique with the combination of crystallization plus phase transformation. Crystallization into ECUT-68 is found to show almost 100% selective uptake of Th(IV) over rare earth and UO22+ ions, while multistep phase transformation from metal-organic frameworks (MOFs) to inorganic compounds is found to directly generate inorganic Th(IV) compound and then Th(IV) solution, suggesting its superior application in the generation of high-purity thorium.

A Novel Functionalized Ionic Liquid for Highly Selective Extraction of TcO4.

Due to the highly acidic and high-salinity nature of the high-level radioactive waste liquid (HLLW), selective extraction of TcO4- from HLLW remains to be a challenging task. Traditional anion exchangers show low selectivity and unsatisfactory extraction performance due to the lack of functional groups that can interact strongly with TcO4-. In this work, a tailor-made binding site was constructed by decorating two acetamide functional groups on imidazolium cation to fabricate a new Tc separation material, which exhibits high selectivity. Unlike most reported Tc separation materials, which can only perform well under low acidic, neutral, or alkaline conditions, this material still has good extraction performance in highly acidic solutions. In the simulated high-level waste liquid of 3 M nitric acid, the extraction efficiency of 0.5 mol/L organic phase for Tc can reach 96.5% through the first-stage extraction. Our theoretical simulations suggest that ReO4-/TcO4- anions were adsorbed on the top of the imidazolium ring during the extraction process, with p-π and p-p interactions acting as the driving forces.

Pt-Chitosan-TiO2 for Efficient Photocatalytic Hydrogen Evolution via Ligand-to-Metal Charge Transfer Mechanism under Visible Light.

The Pt-chitosan-TiO2 charge transfer (CT) complex was synthesized via the sol-gel and impregnation method. The synthesized photocatalysts were thoroughly characterized, and their photocatalytic activity were evaluated toward H2 production through water reduction under visible-light irradiation. The effect of the preparation conditions of the photocatalysts (the degree of deacetylation of chitosan, addition amount of chitosan, and calcination temperature) on the photocatalytic activity was discussed. The optimal Pt-10%DD75-T200 showed a H2 generation rate of 280.4 µmol within 3 h. The remarkable visible-light photocatalytic activity of Pt-chitosan-TiO2 was due to the CT complex formation between chitosan and TiO2, which extended the visible-light absorption and induced the ligand-to-metal charge transfer (LMCT). The photocatalytic mechanism of Pt-chitosan-TiO2 was also investigated. This paper outlines a new and facile pathway for designing novel visible-light-driven photocatalysts that are based on TiO2 modified by polysaccharide biomass wastes that are widely found in nature.

Pan-cancer characterization of metabolism-related biomarkers identifies potential therapeutic targets.

BACKGROUND: Generally, cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. However, the mutual relationship between two critical metabolic pathways, glycolysis and oxidative phosphorylation (OXPHOS), remains poorly defined. METHODS: We developed a "double-score" system to quantify glycolysis and OXPHOS in 9668 patients across 33 tumor types from The Cancer Genome Atlas and classified them into four metabolic subtypes. Multi-omics bioinformatical analyses was conducted to detect metabolism-related molecular features. RESULTS: Compared with patients with low glycolysis and high OXPHOS (LGHO), those with high glycolysis and low OXPHOS (HGLO) were consistently associated with worse prognosis. We identified common dysregulated molecular features between different metabolic subgroups across multiple cancers, including gene, miRNA, transcription factor, methylation, and somatic alteration, as well as investigated their mutual interfering relationships. CONCLUSION: Overall, this work provides a comprehensive atlas of metabolic heterogeneity on a pan-cancer scale and identified several potential drivers of metabolic rewiring, suggesting corresponding prognostic and therapeutic utility.

Multi-omics characterization and validation of invasiveness-related molecular features across multiple cancer types.

BACKGROUND: Tumor invasiveness reflects many biological changes associated with tumorigenesis, progression, metastasis, and drug resistance. Therefore, we performed a systematic assessment of invasiveness-related molecular features across multiple human cancers. MATERIALS AND METHODS: Multi-omics data, including gene expression, miRNA, DNA methylation, and somatic mutation, in approximately 10,000 patients across 30 cancer types from The Cancer Genome Atlas, Gene Expression Omnibus, PRECOG, and our institution were enrolled in this study. RESULTS: Based on a robust gene signature, we established an invasiveness score and found that the score was significantly associated with worse prognosis in almost all cancers. Then, we identified common invasiveness-associated dysregulated molecular features between high- and low-invasiveness score group across multiple cancers, as well as investigated their mutual interfering relationships thus determining whether the dysregulation of invasiveness-related genes was caused by abnormal promoter methylation or miRNA expression. We also analyzed the correlations between the drug sensitivity data from cancer cell lines and the expression level of 685 invasiveness-related genes differentially expressed in at least ten cancer types. An integrated analysis of the correlations among invasiveness-related genetic features and drug response were conducted in esophageal carcinoma patients to outline the complicated regulatory mechanism of tumor invasiveness status in multiple dimensions. Moreover, functional enrichment suggests the invasiveness score might serve as a predictive biomarker for cancer patients receiving immunotherapy. CONCLUSION: Our pan-cancer study provides a comprehensive atlas of tumor invasiveness and may guide more precise therapeutic strategies for tumor patients.

Knockdown of GTF2E2 inhibits the growth and progression of lung adenocarcinoma via RPS4X in vitro and in vivo.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common malignancies worldwide. However, the molecular mechanism of LUAD tumorigenesis and development remains unclear. The purpose of this study was to comprehensively illustrate the role of GTF2E2 in the growth and progression of LUAD. METHODS AND MATERIALS: We obtained the mRNA expression data from The Cancer Genome Atlas, Gene Expression Omnibus database, and our institution. Systematic bioinformatical analyses were performed to investigate the expression and prognostic value of GTF2E2 in LUAD. The results were validated by immunohistochemistry and qPCR. The effect of knocking down GTF2E2 using two short hairpin RNAs was investigated by in vitro and in vivo assays. Subsequently, shotgun liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses were applied to identified potential GTF2E2 interacting proteins, and the downstream molecular mechanisms of GTF2E2-signaling were further explored by a series of cellular functional assays. RESULTS: We found that GTF2E2 expression was significantly increased in LUAD tissue compared with adjacent normal tissue and was negatively associated with patients' overall survival. Besides, we demonstrated that GTF2E2 knockdown inhibited LUAD cell proliferation, migration, invasion, and promote apoptosis in vitro, as well as attenuated tumor growth in vivo. Results from LC-MS/MS suggested that RPS4X might physically interact with GTF2E2 and mediated GTF2E2's regulatory effect on LUAD development through the mTOR pathway. CONCLUSION: Our findings indicate that GTF2E2 promotes LUAD development by activating RPS4X. Therefore, GTF2E2 might serve as a promising biomarker for the diagnosis and prognosis of LUAD patients, thus shedding light on the precise and personalized therapy for LUAD in the future.