• Circ RNA-protein interaction
• castrate-resistant prostate cancer (CRPC)
• drug delivery
• metastasis
• miR-sponging
• review
• siRNA

• Male
• Humans
• RNA, Circular/genetics
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/therapy
• Animals
• Gene Expression Regulation, Neoplastic
• Disease Models, Animal

• NSCLC
• Polymorphisms
• SNP-SNP interaction
• miR-21

• Humans
• MicroRNAs/genetics
• Carcinoma, Non-Small-Cell Lung/genetics
• Polymorphism, Single Nucleotide
• Lung Neoplasms/genetics
• Male
• Middle Aged
• Female
• Genetic Predisposition to Disease
• Aged
• Case-Control Studies
• Genotype

• Metastasis
• Prostate cancer progression
• Therapeutic targets
• mCRPC
• miR-21

• Humans
• MicroRNAs/genetics
• Male
• Disease Progression
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms, Castration-Resistant/pathology
• Prostatic Neoplasms, Castration-Resistant/genetics
• Prostatic Neoplasms, Castration-Resistant/metabolism
• Neoplasm Metastasis
• Gene Expression Regulation, Neoplastic
• Prognosis

• Cancer
• Cuproptosis
• Cuproptosis-related genes
• Targeted therapy

• bioinformatics analysis
• cancer development
• cuproptosis
• hub gene
• prostate cancer

• Cuproptosis
• Gastric cancer
• Immunotherapy
• Prognosis
• Tumor microenvironment

• Humans
• Stomach Neoplasms/genetics
• Stomach Neoplasms/therapy
• Tumor Microenvironment/genetics
• Prognosis
• Immunotherapy
• Nomograms
• Apoptosis

• No. 2042022kf1127 the Fundamental Research Funds for the Central Universities
• grant no. ZNYB2021012 the Program of Excellent Doctoral (Postdoctoral) of Zhongnan Hospital of Wuhan University
• Grant No. ZLYNXM202017 Wuhan University Zhongnan Hospital difficult disease diagnosis and treatment capacity improvement project (oncology)
• No. 2020CFB299 the Natural Science Foundation of Hubei Province
• Grant No. KYXM2022007 Special Project of knowledge Innovation of Wuhan Science and Technology Bureau (Dawning project)

• copper
• cuproptosis
• cuproptosis-related genes
• inflammation
• osteoporosis

• Humans
• Bone Resorption/metabolism
• Copper
• Osteoclasts/metabolism
• Osteoporosis/pathology
• Parathyroid Hormone/metabolism
• Apoptosis

• National Key Research and Development Program of China

• Humans
• Mice
• Animals
• Acetyltransferases/genetics
• Non-alcoholic Fatty Liver Disease
• HEK293 Cells
• Ubiquitination
• Ubiquitin-Protein Ligases/metabolism
• Oxidoreductases/metabolism
• Lipids
• Acetyl-CoA C-Acetyltransferase/genetics

• R01 DK115740 NIDDK NIH HHS
• R01 DK130342 NIDDK NIH HHS
• R01 DK116806 NIDDK NIH HHS
• R01 DK125081 NIDDK NIH HHS
• R01 GM104498 NIGMS NIH HHS
• R01 DK118106 NIDDK NIH HHS
• National Science Foundation
• Science and Technology Commission of Shanghai Municipality
• National Natural Science Foundation of China
• National Institute of Diabetes and Digestive and Kidney Diseases
• National Institute of General Medical Sciences

• Humans
• Tumor Microenvironment/genetics
• Apoptosis
• Chemotherapy, Adjuvant
• Immunotherapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy

• National Natural Science Foundation of China

• PDHA1
• breast cancer
• cuproptosis
• immune infiltration
• prognosis

• breast carcinoma
• cuproptosis
• prognostic model
• tumor immune microenvironment

• LUAD
• cuproptosis
• immune infiltration
• molecular subtypes
• prognosis
• tumor microenvironment

• National Natural Science Foundation of China

• glucose metabolic pathways
• microRNA21
• oocyte maturation
• pig
• reproduction

• cuproptosis
• immunotherapy
• neuroblastoma
• prognosis
• tumor immune microenvironment

• Child
• Humans
• Copper
• Immune Checkpoint Inhibitors
• Neuroblastoma/pathology
• Prognosis
• RNA, Messenger
• Apoptosis

• Natural Science Foundation of Chongqing
• Science-Health Joint Medical Scientific Research Project of Chongqing
• Chongqing Medical University

Lung adenocarcinoma (LUAD) is the most ordinary histological subtype of lung cancer, and regulatory cell death is an attractive target for cancer therapy. Recent reports suggested that cuproptosis is a novel copper-dependent modulated form of cell death dependent on mitochondrial respiration. However, the role of cuproptosis-related genes (CRGs) in the LUAD process is unclear. In the current study, we found that DLD, LIAS, PDHB, DLAT and LIPA1 in 10 differentially expressed CRGs were central genes. GO and KEGG enrichment results showed that these 10 CRGs were mainly enriched in acetyl-CoA biosynthetic process, mitochondrial matrix, citrate cycle (TCA cycle) and pyruvate metabolism. Furthermore, we constructed a prognostic gene signature model based on the six prognostic CRGs, which demonstrated good predictive potential. Excitedly, we found that these six prognostic CRGs were significantly associated with most immune cell types, with DLD being the most significant (19 types). Significant correlations were noted between some prognostic CRGs and tumor mutation burden and microsatellite instability. Clinical correlation analysis showed that DLD was related to the pathological stage, T stage, and M stage of patients with LUAD. Lastly, we constructed the lncRNA UCA1/miR-1-3p/DLD axis that may play a key role in the progression of LUAD and screened nine active components of traditional Chinese medicine (TCM) that may regulate DLD. Further, in vitro cell experiments and molecular docking were used to verify this. In conclusion, we analyzed the potential value of CRGs in the progression of LUAD, constructed the potential regulatory axis of ceRNA, and obtained the targeted regulatory TCM active ingredients through comprehensive bioinformatics combined with experimental validation strategies. This work not only provides new insights into the treatment of LUAD but also includes a basis for the development of new immunotherapy drugs that target cuproptosis.

• National Natural Science Foundation of China

• autoimmune disease
• cuproptosis
• cuproptosis-related genes
• inflammation
• rheumatoid arthritis

• Humans
• Arthritis, Rheumatoid
• Copper/metabolism
• Inflammation/metabolism
• Synoviocytes/metabolism
• Synovitis/pathology
• Apoptosis

Background: Colorectal cancer (CRC) is a heterogeneous disease with many somatic mutations defining its genomic instability. Alternative Splicing (AS) events, are essential for maintaining genomic instability. However, the role of genomic instability-related AS events in CRC has not been investigated.

Methods: From The Cancer Genome Atlas (TCGA) program, we obtained the splicing profiles, the single nucleotide polymorphism, transcriptomics, and clinical information of CRC. Combining somatic mutation and AS events data, a genomic instability-related AS signature was constructed for CRC. Mutations analyses, clinical stratification analyses, and multivariate Cox regression analyses evaluated this signature in training set. Subsequently, we validated the sensitivity and specificity of this prognostic signature using a test set and the entire TCGA dataset. We constructed a nomogram for the prognosis prediction of CRC patients. Differentially infiltrating immune cells were screened by using CIBERSORT. Inmmunophenoscore (IPS) analysis was used to evaluate the response of immunotherapy. The AS events-related splicing factors (SF) were analyzed by Pearson’s correlation. The effects of SF regulating the prognostic AS events in proliferation and migration were validated in Caco2 cells.

Results: A prognostic signature consisting of seven AS events (PDHA1-88633-ES, KIAA1522-1632-AP, TATDN1-85088-ES, PRMT1-51042-ES, VEZT-23786-ES, AIG1-77972-AT, and PHF11-25891-AP) was constructed. Patients in the high-risk score group showed a higher somatic mutation. The genomic instability risk score was an independent variable associated with overall survival (OS), with a hazard ratio of a risk score of 1.537. The area under the curve of receiver operator characteristic curve of the genomic instability risk score in predicting the OS of CRC patients was 0.733. Furthermore, a nomogram was established and could be used clinically to stratify patients to predict prognosis. Patients defined as high-risk by this signature showed a lower proportion of eosinophils than the low-risk group. Patients with low risk were more sensitive to anti-CTLA4 immunotherapy. Additionally, HSPA1A and FAM50B were two SF regulating the OS-related AS. Downregulation of HSPA1A and FAM50B inhibited the proliferation and migration of Caco2 cells.

Conclusion: We constructed an ideal prognostic signature reflecting the genomic instability and OS of CRC patients. HSPA1A and FAM50B were verified as two important SF regulating the OS-related AS.

• National Natural Science Foundation of China

• cancer microenvironment
• cancer therapy
• tumour biomarkers

Altered lipid metabolism is a potential target for therapeutic intervention in cancer. Overexpression of Fatty Acid Synthase (FASN) correlates with poor prognosis in colorectal cancer (CRC). While multiple studies show that upregulation of lipogenesis is critically important for CRC progression, the contribution of FASN to CRC initiation is poorly understood. We utilize a C57BL/6-Apc/Villin-Cre mouse model with knockout of FASN in intestinal epithelial cells to show that the heterozygous deletion of FASN increases mouse survival and decreases the number of intestinal adenomas. Using RNA-Seq and gene set enrichment analysis, we demonstrate that a decrease in FASN expression is associated with inhibition of pathways involved in cellular proliferation, energy production, and CRC progression. Metabolic and reverse phase protein array analyses demonstrate consistent changes in alteration of metabolic pathways involved in both anabolism and energy production. Downregulation of FASN expression reduces the levels of metabolites within glycolysis and tricarboxylic acid cycle with the most significant reduction in the level of citrate, a master metabolite, which enhances ATP production and fuels anabolic pathways. In summary, we demonstrate the critical importance of FASN during CRC initiation. These findings suggest that targeting FASN is a potential therapeutic approach for early stages of CRC or as a preventive strategy for this disease.

• Apc mutation
• colorectal cancer
• colorectal cancer initiation
• fatty acid synthase
• lipid metabolism

Esophageal cancer (EC) is a lethal digestive tumor worldwide with a dismal clinical outcome. Endoplasmic reticulum (ER) stress poses essential implications for a variety of tumor malignant behaviors. Here, we set up an ER stress-based risk classifier for assessing patient outcome and exploiting robust targets for medical decision-making of EC cases.

340 EC cases with transcriptome and survival data from two independent public datasets (TCGA and GEO) were recruited for this project. Cox regression analyses were employed to create a risk classifier based on ER stress-related genes (ERGs) which were strongly linked to EC cases' outcomes. Then, we detected and confirmed the predictive ability of our proposed classifier via a host of statistical methods, including survival analysis and ROC method. In addition, immune-associated algorithm was implemented to analyze the immune activity of EC samples.

Four EGRs (BCAP31, HSPD1, PDHA1, and UBE2D1) were selected to build an EGR-related classifier (ERC). This classifier could distinguish the patients into different risky subgroups. The remarkable differences in patient outcome between the two groups were observed, and similar results were also confirmed in GEO cohort. In terms of the immune analysis, the ERC could forecast the infiltration level of immunocytes, such as Tregs and NK cells.

We created a four-ERG risk classifier which displays the powerful capability of survival evaluation for EC cases.

Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.

• cancer metabolism
• drug resistance
• epithelial mesenchymal transition
• lung cancer
• pyruvate dehydrogenase complex

• PIK3R1
• lung adenocarcinoma
• miR-21-5p
• survival

• diffuse gastric cancer
• gastric cancer
• intestinal gastric cancer
• mass spectrometry
• proteomics
• signet ring cell carcinoma

Despite extensive research, the exact mechanisms involved in colorectal cancer (CRC) etiology and pathogenesis remain unclear. This study aimed to examine the correlation between tumor-associated alternative splicing (AS) events and tumor immune infiltration (TII) in CRC. We analyzed transcriptome profiling and clinical CRC data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq and Innate databases, respectively to develop and validate a risk model of differential AS events and subsequently a TII risk model. We then conducted a two-factor survival analysis to study the association between TII and AS risk and evaluated the associations between immune signatures and six types of immune cells based on the TIMER database. Subsequently, we studied the distribution of six types of TII cells in high- and low-risk groups for seven AS events and in total. We obtained the profiles of AS events/genes for 484 patients, which included 473 CRC tumor samples and 41 corresponding normal samples, and detected 22581 AS events in 8122 genes. Exon Skip (ES) (8446) and Mutually Exclusive Exons (ME) (74) exhibited the most and fewest AS events, respectively. We then classified the 433 patients with CRC into low-risk (n = 217) and high-risk (n = 216) groups based on the median risk score in different AS events. Compared with patients with low-risk scores (mortality = 11.8%), patients with high-risk scores were associated with poor overall survival (mortality = 27.6%). The risk score, cancer stage, and pathological stage (T, M, and N) were closely correlated with prognosis in patients with CRC (P < 0.001). We identified 6479 differentially expressed genes from the transcriptome profiles of CRC and intersected 468 differential immune-related signatures. High-AS-risk and high-TII-risk predicted a poor prognosis in CRC. Different AS types were associated with different TII risk characteristics. Alternate Acceptor site (AA) and Alternate Promoter (AP) events directly affected the concentration of CD4T cells, and the level of CD8T cells was closely correlated with Alternate Terminator (AT) and Exon Skip (ES) events. Thus, the concentration of CD4T and CD8T cells in the CRC immune microenvironment was not specifically modulated by AS. However, B cell, dendritic cell, macrophage, and neutrophilic cell levels were strongly correlated with AS events. These results indicate adverse associations between AS event risk levels and immune cell infiltration density. Taken together, our findings show a clear association between tumor-associated alternative splicing and immune cell infiltration events and patient outcome and could form a basis for the identification of novel markers and therapeutic targets for CRC and other cancers in the future.

• alternative splicing
• colorectal cancer
• immunotherapy
• prognosis
• tumor immune infiltration

• gastric cancer
• microRNAs
• clinical applications

• Biomarkers, Tumor/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Prognosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology

• carcass characteristics
• intensive fattening
• meat quality
• nutritional value
• total mixed rations (TMR)
• yak

Cell migration is an important factor influencing the treatment outcomes of high-grade glioma (World Health Organization grades III–IV). Using immunohistochemical staining, the present study demonstrated that the protein levels of phosphorylated pyruvate dehydrogenase α1 (p-PDHA1) were increased according to the grade of glioma. Moreover, p-PDHA1 mediated tumor necrosis factor-α (TNF-α)-induced cell migration in glioma cells. Phalloidin staining and western blot analysis were used to detect the protein level of p-PDHA1 in U251 glioma cells stimulated by TNF-α at different time points. Phalloidin staining was used to observe the cytoskeletal structure. The effects on the expression of specific migration markers and on the cytoskeletal structure were also detected. Dichloroacetic acid is an inhibitor of PDK. These results indicated that p-PDHA1 served an important role in the migration of glioma cells, and consequently in the development of glioma.

• glioma
• migration
• phosphorylated-pyruvate dehydrogenase α1
• tumor necrosis factor-α

• immune infiltration
• necroptosis
• prognostic signature
• stomach adenocarcinoma

The “Warburg effect” describes the reprogramming of glucose metabolism away from oxidative phosphorylation toward aerobic glycolysis, and it is one of the hallmarks of cancer cells. Several factors can be involved in this process, but in this review, the roles of non-coding RNAs (ncRNAs) are highlighted in several types of human cancer. ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, can all affect metabolic enzymes and transcription factors to promote glycolysis and modulate glucose metabolism to enhance the progression of tumors. In particular, the 5′-AMP-activated protein kinase (AMPK) and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways are associated with alterations in ncRNAs. A better understanding of the roles of ncRNAs in the Warburg effect could ultimately lead to new therapeutic approaches for suppressing cancer.

• Warburg effect
• cancer
• glycolysis
• non-coding RNAs

• gastric cancer
• glycolysis
• mitochondrial dysfunction
• monoamine oxidase A

The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.

Diabetes mellitus is a metabolic disorder predominantly caused by the dysfunction of pancreatic β-cells. This dysfunction is partly caused by the dysregulation of pyruvate dehydrogenase (PDH), which acts as an important mediator of pyruvate oxidation after glycolysis and fuels the tricarboxylic acid cycle. Previous studies have reported decreased PDH expression in rodent models and humans with type 2 diabetes mellitus (T2DM), suggesting that PDH may play an important role in the development of T2DM. However, the mechanism by which PDH affects insulin secretion and β-cell development is poorly understood. Using immunofluorescence staining, the present study found that the expression of pyruvate dehydrogenase E1-α subunit (PDHA1; encoded by the PDHA1 gene) in the islets of type 2 diabetic mice (db/db mice) was lower than in wild-type mice, which indicated the possible association between PDHA1and diabetes. To further understand this mechanism, an inducible, islet-specific PDHA1 knockout mouse (βKO) model was established. The phenotype was authenticated, and the blood glucose levels and islet function between the βKO and control mice were compared. Though no changes were found in food intake, development status, fasting blood glucose or weight between the groups, the level of insulin secretion at 30 min after glucose injection in the βKO group was significantly lower compared with the control group. Furthermore, the performed of the βKO mice on the intraperitoneal glucose tolerance test was visibly impaired when compared with the control mice. Pancreatic tissues were collected for hematoxylin and eosin staining, immunohistochemical and confocal laser-scanning microscopy analysis. Examination of the islets from the βKO mouse model indicated that abolishing the expression of PDH caused a compensatory islet enlargement and impaired insulin secretion.

Ulcerative colitis (UC), a major type of inflammatory bowel disease, is also a chronic non-specific intestinal inflammation condition of unknown etiology. The pathogenesis of UC is closely associated with immune abnormalities, inflammatory damage and genetics. The present study aimed to explore the effects of microRNA (miR)-21-5p on the interleukin-6 (IL-6) receptor (IL6R)/signal transducer and activator of transcription (STAT3) signal pathway in UC, in order to identify a highly effective treatment for UC. A total of 45 patients with UC and 45 healthy controls were recruited for the present study. The expression levels of miR-21-5p and STAT3 in the sera of patients with UC and healthy controls were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A UC rat model was established using dextran sulfate sodium. Following lipopolysaccharide (LPS) treatment, RAW264.7 cells were transfected with a miR-21-5p inhibitor. The levels of morphological damage and apoptosis of the colonic mucosal epithelial tissue were investigated using hematoxylin and eosin staining and a TUNEL staining assay, and then the colon macroscopic damage index and disease activity index were measured in rats. Western blot analysis was used to detect the protein expression levels of IL6R, STAT3, intracellular adhesion molecule 1 (ICAM-1), NF-κB, cleaved caspase-3, cleaved caspase-9 and Fas ligand (FasL). RT-qPCR detected the mRNA expression levels of miR-21-5p, IL6R, STAT3, ICAM-1, NF-κB, caspase-3, caspase-9 and FasL. An ELISA was performed to measure the levels of inflammatory cytokines. The viability and apoptosis levels of RAW264.7 cells were examined using MTT and flow cytometry assays. Additionally, STAT3 was investigated as a direct target of miR-21-5p in RAW264.7 cells using a dual-luciferase reporter assay. The results of the present study demonstrated that inflammation and apoptotic markers were revealed to be significantly downregulated following transfection with miR-21-5p inhibitors in RAW264.7 cells induced by LPS, and that cell viability was increased. Furthermore, STAT3 was confirmed to be a target of miR-21-5p in RAW264.7 cells. Collectively, these data demonstrated that miR-21-5p inhibition mediated the IL-6/STAT3 pathway in UC rats to decrease the levels of inflammation and apoptosis in RAW264.7 cells, and suggested that miR-21-5p may be an important therapy target in human UC.

• apoptosis
• inflammatory
• microRNA-21-5p
• signal transducer and activator of transcription 3
• ulcerative colitis