• Aspirin
• Colitis
• Colon Cancer
• Dclk1
• Stem Cells

• K01 DK133666 NIDDK NIH HHS

• Colon cancer
• Drug predict
• Mitotic
• Prognostic signature
• Tumor microenvironment

• Immune
• RNA sequencing
• Single-cell
• Transcription factors
• Ulcerative colitis

• bioinformatics
• gene expression omnibus
• machine learning
• potential crucial genes
• psoriasis
• ulcerative colitis

• Humans
• Colitis, Ulcerative/genetics
• Machine Learning
• Computational Biology
• Chitinases

• 82273541 National Natural Science Foundation of China
• 2021ZDLSF03-01 Fund of Shaanxi Province
• National Natural Science Foundation of China

• biomarker
• immune-related mechanism
• integrated bioinformatic analyses
• remission
• ulcerative colitis
• weighted gene co-expression network analysis

• Humans
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/genetics
• Inflammation
• Calgranulin B
• Colectomy
• Computational Biology

• Fraxini cortex
• In vivo studies
• Molecular docking
• Network pharmacology
• Ulcerative colitis

• 81774034 National Natural Science Foundation of China
• 2108085MH315 Natural Science Foundation of Anhui Province of China
• gxyq2019030 Outstanding Youth Project of Anhui Institution of Higher Education
• 2022AH050522 Natural Science Foundation of Anhui Institution of Higher Education

• ZEB transcription factors
• adaptation to chronic-inflammation-associated oxidative stress
• inflammatory bowel disease progression
• intestinal cell reprogramming

• colon cancer
• death-associated protein kinase
• differential-gene expression
• dysplasia
• ulcerative colitis
• zipper-interacting protein kinase

Patients with ulcerative colitis are at an increased risk of developing colorectal cancer with a prolonged disease course. Many studies have shown that alterations in the immune microenvironment play a key role in ulcerative colitis-associated colorectal cancer. Additionally, competing endogenous RNAs have important functions in immunoregulation, affecting inflammation and tumorigenesis. However, the complexity and behavioral characteristics of the competing endogenous RNA immunoregulatory network in ulcerative colitis-associated colorectal cancer remain unclear. We constructed a competing endogenous RNA immunoregulatory network to discover and validate a novel competing endogenous RNA immunoregulatory axis to provide insight into ulcerative colitis-associated colorectal cancer progression.

The competing endogenous RNA immunoregulatory network was constructed using differential expression analysis, weighted gene co-expression network analysis, and immune-related genes. Cmap was used to identify small-molecule drugs with therapeutic potential in ulcerative colitis-associated colorectal cancer. The ulcerative colitis-associated colorectal cancer-related pathways were identified by gene set variation and enrichment analysis. CIBERSORT, single-sample Gene Set Enrichment Analysis, and xCell were used to evaluate the infiltration of immune cells and screen hub immunocytes. The competing endogenous RNA immunoregulatory axis was identified by correlation analysis.

We identified 130 hub immune genes and constructed a competing endogenous RNA immunoregulatory network consisting of 56 long non-coding RNAs, four microRNAs, and six targeted hub immune genes. Four small-molecule drugs exerted potential therapeutic effects by reversing the expression of hub immune genes. Pathway analysis showed that the NF-κB pathway was significantly enriched. Neutrophils were identified as hub immunocytes, and IL6ST was significantly positively correlated with the neutrophil count. In addition, NEAT1 may serve as a competing endogenous RNA to sponge miR-1-3p and promote IL6ST expression.

The competing endogenous RNA immunoregulatory axis may regulate neutrophil infiltration, affecting the occurrence of ulcerative colitis-associated colorectal cancer.

The online version contains supplementary material available at 10.1186/s12876-022-02252-7.

• claudin
• barrier function
• inflammation
• colon cancer
• colitis
• tight junction
• vitamin d
• vitamin d receptor

Based on the rapid increase in incidence of inflammatory bowel disease (IBD), the identification of susceptibility genes and cell populations contributing to this condition is essential. Previous studies suggested multiple genes associated with the susceptibility of IBD; however, due to the analysis of whole-tissue samples, the contribution of individual cell populations remains widely unresolved. Single-cell RNA sequencing (scRNA-seq) provides the opportunity to identify underlying cellular populations. We determined the enrichment of Crohn’s disease (CD)-induced genes in a publicly available Crohn’s disease scRNA-seq dataset and detected the strongest induction of these genes in innate lymphoid cells (ILC1), highly activated T cells and dendritic cells, pericytes and activated fibroblasts, as well as epithelial cells. Notably, these genes were highly enriched in IBD-associated neoplasia, as well as sporadic colorectal cancer (CRC). Indeed, the same six cell populations displayed an upregulation of CD-induced genes in a CRC scRNA-seq dataset. Finally, after integrating and harmonizing the CD and CRC scRNA-seq data, we demonstrated that these six cell types display a gradual increase in gene expression levels from a healthy state to an inflammatory and tumorous state. Together, we identified cell populations that specifically upregulate CD-induced genes in CD and CRC patients and could, therefore, contribute to inflammation-associated tumor development.

• Colitis, Ulcerative/pathology
• Colorectal Neoplasms/pathology
• Crohn Disease/pathology
• Humans
• Immunity, Innate
• Inflammation/complications
• Inflammation/genetics
• Inflammatory Bowel Diseases/pathology
• Lymphocytes/pathology

• T32 DK007198 NIDDK NIH HHS
• DK007198-46 NIDDK NIH HHS

• LCN2
• colorectal cancer
• long-duration disease
• ulcerative colitis
• ulcerative colitis-associated carcinogenesis

• National Key Research and Development Program of China

• drug repurposing
• gene expression
• multi-cohort analysis, ulcerative colitis, electronic health records
• transcriptomics

• RNA sequencing
• TPD52L1
• adenoma-carcinoma sequence
• colorectal cancer
• dynamic expression patterns

• ELTD1
• MMP2
• colorectal cancer
• invasion
• metastasis

Modeling human diseases as networks simplify complex multi-cellular processes, helps understand patterns in noisy data that humans cannot find, and thereby improves precision in prediction. Using Inflammatory Bowel Disease (IBD) as an example, here we outline an unbiased AI-assisted approach for target identification and validation. A network was built in which clusters of genes are connected by directed edges that highlight asymmetric Boolean relationships. Using machine-learning, a path of continuum states was pinpointed, which most effectively predicted disease outcome. This path was enriched in gene-clusters that maintain the integrity of the gut epithelial barrier. We exploit this insight to prioritize one target, choose appropriate pre-clinical murine models for target validation and design patient-derived organoid models. Potential for treatment efficacy is confirmed in patient-derived organoids using multivariate analyses. This AI-assisted approach identifies a first-in-class gut barrier-protective agent in IBD and predicted Phase-III success of candidate agents.

Traditional drug discovery process use differential, Bayesian and other network based approaches. We developed a Boolean approach for building disease maps and prioritizing pre-clinical models to discover a first-in-class therapy to restore and protect the leaky gut barrier in inflammatory bowel disease.

• cancer risk
• inflammatory bowel disease
• molecular biomarkers
• molecular risk factors
• risk factors

• 19771 Cancer Research UK

• H2Bub1
• SPARC
• USP22
• colorectal cancer
• epigenetics
• inflammatory bowel diseases

• 000000 Mildred Scheel postdoc fellowship
• R01 AI089714 NIAID NIH HHS
• 70113213 Max Eder Fellowship
• 00000000 DFG Clinician Scientist Fellowship
• 413501650 Deutsche Forschungsgemeinschaft
• 00000000 Erich und Gertrud Roggenbuck-Stiftung
• 2157/2-1 KFO5002 Deutsche Forschungsgemeinschaft

• colitis-associated colorectal cancer; CAC
• diagnostic model
• remission
• ulcerative colitis; UC

Ulcerative colitis (UC) is a chronic, highly heterogeneous intestinal inflammation with changes in epithelial function and tissue damage. However, the pathogenesis is still unclear between active UC and inactive UC. Herein, weighted gene co‐expression network analysis was applied to explore the gene modules related to active UC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to further investigate the underlying mechanism of selected genes. We found that in the blue module (r = −.72), carboxypeptidase A6 (CPA6) was chosen to validate because of its high intra‐modular connectivity and module membership. In the test sets, the expression level of CPA6 was down‐regulated in active UC compared with inactive UC and normal colon. Furthermore, CPA6 expression was decreased primarily in the descending colon and only in mucosa affected by active UC. The receiver operating characteristic curve indicated that CPA6 expression had a performed well in diagnosing active UC from inactive UC (area under the curve = 0.99). Importantly, anti‐tumour necrosis factor (TNF) treatment (infliximab and golimumab) significantly increased the CPA6 expression. Finally, GSEA and GSVA found that extracellular matrix receptor, inflammatory response and epithelial‐mesenchymal transition were highly enriched in active UC with low CPA6 expression. In conclusion, CPA6 was identified and validated as a novel potential biomarker for predicting the occurrence of active UC, probably through regulating extracellular matrix or immune response.

• CPA6
• WGCNA
• active UC
• anti-TNF treatment

• DNA methylation
• Ulcerative colitis
• colon cancer
• gene expression
• inflammatory bowel disease

Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran–sulfate–sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking-down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples (N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound-healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD.

• SUMOylation
• colitis
• epithelial signalling
• inflammation
• post-translational modification

• colorectal cancer
• epigenetics
• genetics
• gut microbiota
• molecule
• ulcerative colitis

Identification of biological markers predicting the onset of neoplasia in patients with long-standing ulcerative colitis (UC) could allow for risk stratification in this population. In this study, we retrospectively identified subjects with chronic UC who developed colon neoplasia (n = 16) matched to UC patients who never developed neoplasia. RNA was extracted from archived colonic biopsies obtained at an interval of 1–2 years prior and 3–5 years prior to the onset of neoplasia. miRNA expression was assessed using Nanostring arrays in 12 subjects, and significantly up-regulated miRNAs were evaluated by real time pcr in the entire cohort of patients. Expression of miR-215 was also assessed in UC-associated colon cancers and compared to p53 expression. By array analysis, there were 17 significantly down-regulated and 7 significantly up-regulated miRNAs in subjects who later developed neoplasia. miR-215 was significantly up-regulated both 1–2 years prior to the onset of neoplasia (3.5-fold, p < 0.001) and 3–5 years prior to the onset of neoplasia (5.4-fold, p = 0.007). miR-215 expression was also increased in UC-associated colon cancers (5.3-fold, p = 0.03) and adjacent non-dysplastic UC tissue (6.2-fold, p = 0.02). p53 was expressed in 20% of patients prior to the onset of neoplasia and in 67% of UC-associated colon cancers, although was not correlated with miR-215 expression. Our data demonstrates that expression of miR-215 can discriminate patients who progressed to neoplasia from non-progressors as early as 5 years prior to the diagnosis of neoplasia, supporting that this and perhaps other miRNAs could serve as predictive biomarkers to risk stratify patients with chronic UC.

• colon cancer
• miRNA
• neoplasia
• predictive biomarker
• ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with both genetic and environmental factors; however, the underlying pathogenesis of UC remains unclear. The present study aimed to further explore 12 microarray datasets from patients with UC obtained from the Gene Expression Omnibus repository, for potential genetic pathogenesis of UC through a global bioinformatics view, which included identification of differentially expressed genes (DEGs), functional enrichments, protein-protein interactions, transcriptional and post-transcriptional regulation and drug-gene associations. This integrated analysis screened 233 DEGs that were compared between UC and normal control tissue samples; these included 173 upregulated and 60 downregulated DEGs. Subsequently, transcription factors, such as TATA-binding protein 1 (TBP1; hsa_TATAAA_V$TATA_01) and nuclear factor-κB (NF-κB; hsa_V$NFKAPPAB_01) and microRNAs (miRNAs; such as miR-516-3p and miR-23a) were revealed to be associated with 233 DEGs. Notably, further analysis indicated that these DEGs were enriched in certain diseases, including inflammation, fibrosis and immune system diseases, and were also associated with some drugs, including prednisone, collagenase and mycophenolate mofetil, which may provide choice for treatment of UC. In conclusion, this study may provide novel insights into discovering potential molecular targets involved in the pathogenesis and treatment of UC.

• mirna
• ulcerative colitis
• inflammatory bowel disease
• focal adhesion
• colon cancer
• dysplasia

• Adult
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Caveolin 1/genetics
• Caveolin 1/metabolism
• Colitis, Ulcerative/complications
• Collagen Type I/genetics
• Collagen Type I/metabolism
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Female
• Focal Adhesions/genetics
• Follow-Up Studies
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• Prognosis
• Signal Transduction
• Thrombospondins/genetics
• Thrombospondins/metabolism

• K08 DK090152 NIDDK NIH HHS
• P30 DK042086 NIDDK NIH HHS

Colorectal cancer (CRC) is a life-threatening complication of ulcerative colitis (UC), and patients are routinely screened for the development of precancerous lesions (dysplasia). However, rates of CRC development in patients with confirmed low-grade dysplasia vary widely between studies, suggesting a large degree of heterogeneity between these lesions that is not detectable macroscopically. A better understanding of the underlying molecular changes that occur in dysplasia will help to identify lesions at higher risk of malignancy. MicroRNAs (miRNAs) post-transcriptionally regulate protein expression and cell-signalling networks. Aberrant miRNA expression is a feature of sporadic CRC but much less is known about the changes that occur in dysplasia and in UC.

Comprehensive microRNA profiling was performed on RNA extracted from UC dysplastic lesions (n = 7) and UC controls (n = 10). The expression of miRNAs in UC post inflammatory polyps (n = 7) was also assessed. Candidate miRNAs were further validated by qPCR, and miRNA in situ hybridization. Serum levels of miRNAs were also assessed with a view to identification of non-invasive biomarkers of dysplasia.

UC dysplasia was associated with a shift in miRNA expression profiles that was not seen in inflammatory polyps. In particular, levels of miR-200b-3p were increased in dysplasia, and this miRNA was localised to epithelial cells in dysplastic lesions and in UC cancers. No changes in miRNA levels were detected in the serum.

UC-Dysplasia is linked to altered miRNA expression in the mucosa and elevated miR-200b-3p levels.

Identification of disease genes is a hot topic in biomedicine and genomics. However, it is a challenging problem because of the complexity of diseases. Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. It has been proven to be associated with the development of intestinal malignancies. Although the specific pathological characteristics and genetic background of IBD have been partially revealed, it is still an overdetermined disease and the blueprint of all genetic variants still needs to be improved. In this study, a novel computational method was built to identify genes related to IBD. Samples from two subtypes of IBD (ulcerative colitis and Crohn's disease) and normal samples were employed. By analyzing the gene expression profiles of these samples using minimum redundancy maximum relevance and incremental feature selection, 21 genes were obtained that could effectively distinguish samples from the two subtypes of IBD and the normal samples. Then, the shortest-path approach was used to search for an additional 20 genes in a large network constructed using protein-protein interactions based on the above-mentioned 21 genes. Analyses of the 41 genes obtained indicate that they are closely associated with this disease.

Patients with extensive ulcerative colitis (UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques - including cutting-edge OMICS technologies - recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.

• Biomarker
• Colitis
• Dysplasia
• Colorectal cancer
• Surveillance
• Progressor
• Non-progressor

• Biomarkers, Tumor/analysis
• Biopsy
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/pathology
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/pathology
• DNA Methylation
• Disease Progression
• Humans
• MicroRNAs/analysis
• Precancerous Conditions/pathology
• Risk Factors

• R21 CA164548 NCI NIH HHS

Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), an orphan adhesion G-protein coupled receptor, was reported as a regulator of angiogenesis, also involved in cancer progression and development. More recently, ELTD1 was identified as a potential new tumor marker for high-grade glioma. ELTD1, belongs to the G-protein coupled receptor superfamily that comprises the biggest receptor family in the human genome. Following the discovery of ELTD1 almost a decade ago, only a few research groups have attempted to find its role in normal and tumor cells, important information about this receptor remaining still unknown. The ELTD1 ligand has not currently been identified and intracellular signaling studies have not yet been performed in normal or tumor cells. Although the current published data on ELTD1 function and structure are rather limited, this receptor seems to be very important, not only as biomarker, but also as molecular target in glioblastoma. This review summarizes and discusses the current knowledge on ELTD1 structure, function, and its role in both physiological and tumoral angiogenesis.

• ELTD1
• angiogenesis
• biomarker
• glioma

Idiopathic inflammatory bowel disease (IBD) predominantly includes ulcerative colitis and Crohn’s disease. The pathogenesis of IBD is complex and not completely understood. MicroRNAs belong to a class of noncoding small RNAs that post-transcriptionally regulate gene expression. Unique microRNA expression profiles have been explored in IBD. In this review, we focus on the unique microRNA expression pattern in both tissue and peripheral blood from IBD patients and emphasize the potential diagnostic and therapeutic applications. The discovery of microRNAs has contributed to our understanding of IBD pathogenesis and might lead to clinical advance in new therapeutics.

• Inflammatory bowel disease
• Ulcerative colitis
• Crohn’s disease
• MicroRNA
• Pathogenesis
• Gene expression

• Animals
• Gene Expression Profiling
• Gene Expression Regulation
• Genetic Markers
• Genetic Predisposition to Disease
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/therapy
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Molecular Diagnostic Techniques
• Phenotype
• Predictive Value of Tests
• Prognosis
• Translational Research, Biomedical

• Adolescent
• Adult
• Aged
• Case-Control Studies
• Child
• Child, Preschool
• Cholangitis, Sclerosing/complications
• Cholangitis, Sclerosing/genetics
• Cohort Studies
• Colitis, Ulcerative/complications
• Colitis, Ulcerative/genetics
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/genetics
• Logistic Models
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Polymorphism, Single Nucleotide
• Young Adult

Ulcerative colitis (UC) was the most frequently diagnosed inflammatory bowel disease (IBD) and closely linked to colorectal carcinogenesis. By far, the underlying mechanisms associated with the disease are still unclear. With the increasing accumulation of microarray gene expression profiles, it is profitable to gain a systematic perspective based on gene regulatory networks to better elucidate the roles of genes associated with disorders. However, a major challenge for microarray data analysis is the integration of multiple-studies generated by different groups.

In this study, firstly, we modeled a signaling regulatory network associated with colorectal cancer (CRC) initiation via integration of cross-study microarray expression data sets using Empirical Bayes (EB) algorithm. Secondly, a manually curated human cancer signaling map was established via comprehensive retrieval of the publicly available repositories. Finally, the co-differently-expressed genes were manually curated to portray the layered signaling regulatory networks.

Overall, the remodeled signaling regulatory networks were separated into four major layers including extracellular, membrane, cytoplasm and nucleus, which led to the identification of five core biological processes and four signaling pathways associated with colorectal carcinogenesis. As a result, our biological interpretation highlighted the importance of EGF/EGFR signaling pathway, EPO signaling pathway, T cell signal transduction and members of the BCR signaling pathway, which were responsible for the malignant transition of CRC from the benign UC to the aggressive one.

The present study illustrated a standardized normalization approach for cross-study microarray expression data sets. Our model for signaling networks construction was based on the experimentally-supported interaction and microarray co-expression modeling. Pathway-based signaling regulatory networks analysis sketched a directive insight into colorectal carcinogenesis, which was of significant importance to monitor disease progression and improve therapeutic interventions.