Ulcerative Colitis-associated Colorectal Cancer Research Articles

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated Colorectal Cancer and Associated Pharmacological Interventions.

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

Exploring the mechanism and key active components of Gegen Qinlian decoction combined with XELOX in the treatment of ulcerative colitis-associated colorectal cancer based on network pharmacology and multi-omics analysis

Ulcerative colitis (UC) is an autoimmune disease with a steady increase in global prevalence and long-term susceptibility to colorectal cancer (CRC). CRC is often treated with XELOX regimen (oxaliplatin and capecitabine), which is limited by the high toxicity, many adverse reactions and intolerance of patients, thus often leading to termination of chemotherapy. Traditional Chinese medicine is effective in improving patients' clinical symptoms. Gegen Qinlian decoction (GQD) is frequently utilized in the management of UC and has the potential to treat CRC. Whereas, there are few studies on GQD in the treatment of UC-associated CRC, and the therapeutic mechanism of GQD combined with XELOX has not been fully reported. Herein, HPLC-Q-TOF-MS/MS technique was used to analyze the main chemical components of GQD. Network pharmacology was performed to unveil the critical genes and components of GQD against UC and UC-associated CRC. The detection of TNF-α, IL-1β, IL-6, VEGF, SOD, MDA and immune factors revealed that GQD played a key role in improving immune function, reducing inflammation and resisting oxidative stress. 16S rDNA sequencing technology results showed that GQD could maintain gastrointestinal homeostasis by increasing beneficial bacteria and decreasing harmful bacteria. Then, metabolomics based on HPLC-Q-TOF-MS/MS found that the combination of GQD and XELOX could significantly restore the disturbance of metabolites. Particularly, the compound-reaction-gene-enzyme network was first constructed to realize the combination of network pharmacology and metabolomics. The results showed that GQD may assist XELOX to play a synergistic anti-tumor role by regulating the key enzymes ALOX15, CYP1B1 and PTGS2 in unsaturated fatty acid metabolism. Finally, the mechanism was verified by western blot, and the key pharmacodynamic components were found by molecular docking. Overall, the current study offered fresh perspectives on both the prevention and treatment of UC to CRC as well as fresh concepts for the therapeutic application of GQD with XELOX to lessen the side effects of chemotherapy and enhance patients' quality of life.

Promoter methylation levels of microRNA-124 in non-neoplastic rectal mucosa as a potential biomarker for ulcerative colitis-associated colorectal cancer in pediatric-onset patients.

To determine the methylation level of the miR-124 promoter in non-neoplastic rectal mucosa of patients with pediatric-onset ulcerative colitis (UC) to predict UC-associated colorectal cancer (UC-CRC). Between 2005 and 2017, non-neoplastic rectal tissue specimens were collected from 86 patients with UC, including 13 patients with UC-CRC; cancer tissues were obtained from the latter group. The methylation status of the miR-124 promoter was quantified using bisulfite pyrosequencing and compared between pediatric- and adult-onset UC patients. Patients with pediatric-onset UC experienced a significantly shorter disease duration than those with adult-onset UC. The levels of miR-124 promoter methylation in non-neoplastic rectal mucosa were positively correlated with the age at the diagnosis and duration of UC. The rate of increase in miR-124 methylation was accelerated in patients with pediatric-onset UC compared to those with adult-onset UC. Furthermore, the miR-124 methylation levels in non-neoplastic rectal mucosa were significantly higher in patients with UC-CRC than in those with UC alone (P = 0.02). A receiver operating characteristic analysis revealed that miR-124 methylation in non-neoplastic tissue discriminated between patients with pediatric-onset UC with or without CRC. miR-124 methylation in non-neoplastic rectal mucosa may be a useful biomarker for identifying patients with pediatric-onset UC who face the highest risk of developing UC-CRC.

Risk factors for the postoperative recurrence of ulcerative colitis-associated colorectal cancer.

Although ulcerative colitis-associated colorectal cancer (UC-CRC) has been described, there are few reports regarding recurrent cases of UC-CRC. In this study, we investigated the risk factors for UC-CRC recurrence. Recurrence-free survival (RFS) was determined for 144 stage I to III cancer patients among 210 UC-CRC patients from August 2002 to August 2019. The Kaplan‒Meier method was used to obtain the cumulative RFS rate, and the Cox proportional hazard model was used to extract recurrence risk factors. The interaction term between cancer stage and prognostic factors specific to UC-CRC was evaluated using the Cox model. The Kaplan‒Meier method was applied by cancer stage to the UC-CRC-specific prognostic factors for which interaction effects were indicated. There were 18 cases of recurrence involving patients with stage I to III cancer, and the recurrence rate was 12.5%. The cumulative 5-year RFS rate was 87.5%. Multivariable analysis showed that age at surgery (hazard ratio (HR): 0.95, 95% CI: 0.91-0.99, p = 0.02), undifferentiated carcinoma (HR: 4.42, 95% CI: 1.13-17.24, p = 0.03), lymph node metastasis (HR: 4.11, 95% CI: 1.08-15.69, p = 0.03), and vascular invasion (HR: 8.01, 95% CI: 1.54-41.65, p = 0.01) were significant risk factors for recurrence. Patients with stage III CRC in the young adult (age < 50years) group had a significantly worse prognosis than those in the adult (age ≥ 50years) group (p < 0.01). Age at surgery was identified as a risk factor for UC-CRC recurrence. Young adult patients with stage III cancer may have a poor prognosis.

Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

BackgroundUlcerative colitis-associated colorectal cancer (UC-CRC) is an important complication of ulcerative colitis. Pou3f1 (POU class 3 homeobox 1) is a critical regulator for developmental events and cellular biological processes. However, the role of Pou3f1 in the development of UC-CRC is unclear.MethodsIn vivo, a UC-CRC mouse model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Body weight, colon length, mucosal damage, tumor formation, and survival rate were assessed to determine the progression of UC-CRC. Western blot, quantitative real-time PCR, ELISA, immunohistochemistry, immunofluorescence and TUNEL were performed to examine the severity of inflammation and tumorigenesis. In vitro, LPS-treated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were used to study the role of Pou3f1 in inflammation. ChIP and luciferase reporter assays were used to confirm the interaction between Nfatc3 and Pou3f1.ResultsPou3f1 expression was increased in the colons of UC-CRC mice, and its inhibition attenuated mucosal injury, reduced colon tumorigenesis and increased survival ratio. Knockdown of Pou3f1 suppressed cell proliferation and increased cell death in colon tumors. Both the in vivo and in vitro results showed that Pou3f1 depletion reduced the production of proinflammation mediators. In addition, ChIP and luciferase reporter assays demonstrated that Nfatc3 directly bound with the Pou3f1 promoter to induce its expression. The effect of Nfatc3 on the inflammatory response in macrophages was suppressed by Pou3f1 knockdown.ConclusionOverall, it outlines that Pou3f1 mediates the role of Nfatc3 in regulating macrophage inflammation and carcinogenesis in UC-CRC development.

A novel ceRNA-immunoregulatory axis based on immune cell infiltration in ulcerative colitis-associated colorectal carcinoma by integrated weighted gene co-expression network analysis

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

Long-Term Outcomes After Colorectal Surgery in Patients with Ulcerative Colitis-Associated Colorectal Cancer Versus Sporadic Colorectal Cancer.

Ulcerative colitis is associated with a higher risk for developing colorectal cancer. It is unknown whether this translates into a worse prognosis when malignancy occurs. The goal of this study was to compare long-term outcomes between patients with ulcerative colitis-associated colorectal cancer and sporadic colorectal cancer. All patients who underwent surgery with curative intent for colorectal cancer in Denmark between January 2004 and June 2016 were included in the study. Patients diagnosed with ulcerative colitis were identified and matched 1:5 with patients with sporadic colorectal cancer using propensity score matching. The primary outcome was disease-free survival, with recurrence-free survival and all-cause mortality as secondary outcomes. In order to relate the results of the study to the existing literature, a systematic review with meta-analysis was conducted. A total of 1332 patients, 222 with ulcerative colitis and 1110 with sporadic colorectal cancer were included in the study. Disease-free survival was similar between the two groups with a hazards ratio (HR) 1.06 [95% confidence interval (CI) 0.85-1.32], as was recurrence-free survival HR 1.14 (95% CI 0.86-1.53) and all-cause mortality HR 1.15 (95% CI 0.89-1.48). The results of the systematic review identified seven other relevant studies. Meta-analysis showed a HR 1.67 (95% CI 0.61-4.56) for recurrence-free survival and HR 1.21 (95% CI 0.93-1.56) for all-cause mortality. There were no significant differences in long-term outcomes between ulcerative colitis-associated and sporadic colorectal cancer. However, the current results are limited by possible residual confounding and the meta-analysis by heterogeneity in confounding adjustment.

Vitexin prevents colitis-associated carcinogenesis in mice through regulating macrophage polarization

BackgroundPatients with inflammatory bowel disease are at increased risks of developing ulcerative colitis-associated colorectal cancer (CAC). Vitexin can suppress the proliferation of colorectal carcinoma cells in vitro orin vivo. However, different from colorectal carcinoma, CAC is more consistent with the transformation from inflammation to cancer in clinical chronic IBD patients. Therefore, we aim to investigated that vitexin whether possess benefic effects on CAC mice. PurposeWe aimed to determine the beneficial effects of vitexin on CAC mice and reveal its underlying mechanism. MethodsThe mouse CAC model was induced by Azoxymethane and dextran sodium sulfate (AOM/DSS) and CAC mice were treated with vitexin. At the end of this study, inflammatory cytokines of IL-1β, IL-6, TNF-α, IL-10 as well as nitric oxide (NO) were detected by kits after long-term treatment of vitexin. Pathological changes and macrophage polarization were determined by H&E and immunofluorescence in adjacent noncancerous tissue and carcinomatous tissue respectively of CAC mice. ResultsOur results showed that oral administration of vitexin could significantly improve the clinical signs and symptoms of chronic colitis, relieve colon damage, regulate colonic inflammatory cytokines, as well as suppress tumor incidence and tumor burden. Interesting, vitexin caused a significant increase in serum level of NO and a higher content of NO in tumor tissue. In addition, vitexin significantly decreased M1 phenotype macrophages in the adjacent noncancerous tissue, while markedly up-regulated M1 macrophage polarization in the tumor tissue in the colon of CAC mice. ConclusionVitexin can attenuate chronic colitis-associated carcinogenesis induced by AOM/DSS in mice and its protective effects are partly associated with its alternations in macrophage polarization in the inflammatory and tumor microenvironment .

The role of FKBP51 in the prognosis of ulcerative colitis-associated colorectal cancer

PurposeUlcerative colitis (UC) carries a high risk of developing colorectal cancer (CRC). FK506-binding protein 51 (FKBP51) is a key regulator of glucocorticoid resistance and inflammatory tumor microenvironment. This study aimed to investigate the role of FKBP51 in UC-CRC prognosis. Materials and methodsThe FKBP51 expression was measured by immunohistochemistry, qRT-PCR and western blot in control and tumor-containing tissues from UC-CRC patients. H&E staining was used to analyze the inflammatory status of each sample. The relationship between FKBP51 expression and UC-CRC prognosis was assessed by Kaplan–Meier curves and Mann-Whitney U test, and receiver-operating characteristic curves were generated to clarify the role of FKBP51 in predicting survival period and recurrence of UC-CRC patients. ResultsThe FKBP51 expression was significantly (p ​< ​0.01) increased by 36.3% in tumor-containing tissues compared to control tissues in UC-CRC patients. Nuclear enrichment of FKBP51 in tumor-containing tissues was significantly (p ​< ​0.001) increased by 78.5%. The UC-CRC patients with higher levels of FKBP51 expression ratio between tumor-containing tissues and control tissues had shorter survival periods, but greater neutrophil invasion and neutrophils to lymphocytes ratio (NLR) in peripheral blood. Moreover, the FKBP51 expression ratio was more helpful in predicting the survival periods and recurrence in the UC-CRC patients than the NLR in peripheral blood. ConclusionsThe FKBP51 expression ratio between tumor-containing tissue and control tissue may be an important biomarker of inflammatory tumor microenvironment and more helpful for the UC-CRC prognosis.

A Seven-NF-κB-Related Gene Signature May Distinguish Patients with Ulcerative Colitis-Associated Colorectal Carcinoma.

PurposeUlcerative colitis (UC) patients have an increased risk of colorectal cancer (CRC), and compared with sporadic CRC, ulcerative colitis-associated colorectal cancer (CAC) is more aggressive with a worse prognosis. This study aimed to identify a gene signature to predict the risk of CAC for patients with UC in remission.Patients and MethodsSeries of quiescent UC-related transcriptome data obtained from the Gene Expression Omnibus (GEO) data set were divided into a training set and a validation set. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and \\Weighted Correlation Network Analysis (WGCNA) combined with protein–protein interaction (PPI) analysis were used to identify the pathways and gene signatures related to tumorigenesis among quiescent UC patients. A generalized linear model (GLM) of Poisson regression based on the training set was applied to estimate the diagnostic power of the gene signature in our validation set.ResultsThe tumor necrosis factor (TNF) signaling via NF-κB pathway was significantly augmented with the highest normalized enrichment score (NES). The genes in the brown module from WGCNA have shown a significant correlation with CAC (Pearson coefficient = 0.83, p = 6e-06). A subset of NF-κB related genes (FOS, CCL4, CXCL1, MYC, CEBPB, ATF3, and JUNB) were identified with a relatively higher expression level in CAC samples. The diagnostic value of this 7-gene biomarker was estimated by the receiver operating characteristic (ROC) curve with an area under the ROC curve (AUC) at 0.82 (p<0.0001, 95% CI: 0.7098–0.9400) in the validation cohort.ConclusionIn summary, the increased expression of this seven-NF-κB-related gene signature may act as a powerful index for tumorigenesis prediction among patients with UC in remission.

Risk factors for ulcerative colitis-associated colorectal cancer: A retrospective cohort study.

Inflammatory bowel disease is associated with an increased risk of colorectal cancer. The study aims to identify the risk factors for ulcerative colitis-colorectal cancer and to perform a survival curve analysis of the outcome.This retrospective cohort study included 254 patients from March 2016 to October 2017. Age, age at diagnosis, follow-up time, smoking status, and family history of colorectal cancer were analyzed as risk factors for colorectal cancer.The mean patient age was 46.6 ± 16.9 years; 5.5% of the patients were smokers and 49.6% had pancolitis. Six patients (2.36%) had colorectal cancer, which was associated with age at diagnosis (odds/hazard ratio 1.059 [95% confidence interval: 1.001–1.121]; P = .04), family history of colorectal cancer (12.992 [1.611–104.7]; P = .02), and follow-up time (0.665 [0.513–0.864]; P = .002). Active smoking was the main identified risk factor, after both logistic (8.477 [1.350–53.232]; P = .02) and Cox proportional-hazards (32.484 [2.465–428.1]; P = .008) regression analysis. The risk of colorectal cancer was 3.17% at 10 years and 4.26% at 20 years of follow-up.Active smoking and family history were identified as risk factors for colorectal cancer. These findings should aid the early identification of patients who require vigorous surveillance, and prevent exposure to risk factors.

Dysplasia in the mucosal biopsy specimen is still a warning sign of cancer in ulcerative colitis

Objectives Patients with ulcerative colitis are at increased risk for colorectal cancer, especially at younger ages. Our aim was to determine, in our patient cohort, the clinicopathological features, incidence, and prognosis of ulcerative colitis-associated colorectal cancer. Materials and methods A single-center, population-based study including all 1241 patients with ulcerative colitis who underwent surgery in Helsinki University Hospital, 1991–2018. All data were from medical records, collected retrospectively. Results In total, 71 patients with ulcerative colitis-associated cancer were operated on in Helsinki University Hospital during 1991–2018; 108 patients undergoing surgery during 2002–2018 showed dysplasia in the surgical specimen. Cancer was diagnosed preoperatively in 47 patients (66.2%). Ten patients (14.1%) had synchronous colorectal cancer, and 24 (33.8%) had synchronous dysplasia. The incidence of colorectal cancer has not changed during the study period (p = .113). Overall survival was 71.8%, and the 5-year colorectal cancer-specific survival was 81.5%. Conclusion The incidence of ulcerative colitis-associated colorectal cancer remained constant in our study population over three decades. The prognosis of ulcerative colitis-associated colorectal cancer and the prognosis of sporadic colorectal cancer were comparable. One-third of the cancers were not diagnosed in preoperative colonoscopy, and the indication for surgery in such cases was dysplasia. We therefore do not recommend the endoscopic management of ulcerative colitis-associated dysplasia.

Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition

Ulcerative colitis-associated colorectal cancer (UC-CRC) is the most serious complication of ulcerative colitis (UC). Nuclear factor of activated T cells 3 (NFATc3) is participated in inflammation and cancer. In this study, we investigated the effects of NFATc3 on experimental UC-CRC in vivo and in vitro, and explored the underlying mechanisms. Administration of azoxymethane (AOM) and dextran sulfate sodium (DSS) induced UC-CRC model in C57BL/6 mice. Body weight was monitored weekly. Colon tissues were harvested at week 14. We examined changes in the histopathology, inflammatory cytokines, carcinogenesis factors, and epithelial-mesenchymal transition (EMT) markers in colon tissues. We found that NFATc3 expression was significantly up-regulated in AOM/DSS treated mice compared with control. Mice lacking NFATc3 showed decreased tumor number and size, decreased mucosal damage, and increased survival rate. Moreover, down-regulation of NFATc3 could inhibit the proliferation and EMT of UC-CRC, decrease the levels of pro-inflammatory cytokines, reduce the colonic infiltration by neutrophils and macrophages, and suppress the activation of P38 and JNK signal pathway in mice. In In vitro experiments, silencing NFATc3 suppressed the proliferation and EMT of CRC cells, and reduced the activation of P38 and JNK. In addition, miR-370-3p could bind to NFATc3. Down-regulation of miR-370-3p promoted proliferation and EMT of CRC cells, while silencing NFATc3 could reverse these effects. In conclusion, NFATc3 was involved in the pathogenesis of experimental UC-CRC and NFATc3 knockdown ameliorated experimental UC-CRC progression via the inhibition of inflammatory responses and EMT. NFATc3 mediated the inhibitory effects of miR-370-3p on CRC cells proliferation and EMT. Targeting NFATc3 may be effective in treating UC-CRC.

Upregulation of Fecal Epithelial Heparanase mRNA Is Associated with Increased Ulcerative Colitis Activity and Cancerization Risk

BackgroundHeparanase (HPSE) is considered to play an important role in the occurrence, development and carcinogenesis of ulcerative colitis (UC). There are no reports about the detection of HPSE mRNA in feces to predict UC activity and cancerization risk.AimsTo explore the feasibility and effectiveness of fecal epithelial HPSE mRNA in monitoring patients’ UC activity and predicting cancer risk.MethodsThe clinical part of the study enrolled 20 patients with UC and 20 controls. Meanwhile, a UC-induced carcinogenesis mouse model was established using a combination treatment of dimethylhydrazine and dextran sulfate sodium. Tissue expression of HPSE protein was detected by immunohistochemistry. RT-qPCR was used to detect the expression of HPSE mRNA in colonic mucosa and feces.ResultsIn the human study, the relative expressions of HPSE mRNA in colonic mucosa and feces were positively correlated with the Mayo score (P < 0.05), and with a significant correlation between feces and colonic mucosa (P < 0.05). In the mouse model, the relative expressions of HPSE mRNA in colonic mucosa and feces in the ulcerative colitis-associated colorectal cancer group was significantly higher than that of the UC group and the normal control group (P < 0.05), and with a significant correlation between feces and colonic mucosa (P < 0.05).ConclusionsThe relative level of HPSE mRNA was positively correlated with UC activity and cancerization. The relative level of HPSE mRNA in feces was correlated with that in colonic mucosa. The detection of HPSE mRNA in feces can be used as a new marker for disease monitoring and cancer risk prediction of UC.

Expression of CA2 and CA9 carbonic anhydrases in ulcerative colitis and ulcerative colitis-associated colorectal cancer.

Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic mucosa and submucosa with repeating relapse and remission, but the pathogenesis is unknown. Patients with long-standing UC are at high risk of neoplasm development. The aim of the present study was to identify molecules whose expression is associated with UC and UC-associated colorectal cancer (UCCA). Biopsy specimens from UC and normal colonic mucosae were analyzed using a proteomics approach, in which carbonic anhydrase 2 (CA2) was identified as a molecule downregulated in UC mucosae. Immunohistochemically, CA2 expression was detected in normal and diverticulitis mucosal epithelia, and its expression decreased as UC activity increased. CA2 expression was almost undetectable in UCCA. We also analyzed the expression of another carbonic anhydrase, CA9, and its upstream molecule, hypoxia-inducible factor-1α (HIF-1α), both of which are induced under hypoxic conditions. It was revealed that CA9 expression was relatively low in normal, diverticulitis and UC mucosae, and was upregulated in UCCA. HIF-1α expression was consistently low in all tissue types examined. In conclusion, these results suggest that CA2 and CA9 may be possible indicators of UC activity and UCCA development, respectively.

Analysis on clinical features of patients with ulcerative colitis associated colorectal cancer

Objective: To analyze the clinical features of ulcerative colitis associated colorectal cancer (UC-CRC). Methods: A total of 869 inpatients with Ulcerative Colitis (UC) in Peking Union Medical Hospital from January 1998 to January 2018 were continuously enrolled. Clinical data and the outcome of colorectal cancer (CRC) were collected via medical records and telephone follow-up. Chi-square test and logistic regression model were used to analyze the data. Results: There were 16 patients in 869 UC inpatients who were diagnosed with CRC during a period of 7 548 person years and the incidence rate of UC-CRC was 1.84%. Compared to UC inpatients without CRC, a longer course of disease (OR=1.087, 95% CI:1.046-1.129) , a lower usage rate of 5-Aminosalicylic Acid(5-ASA) (OR=0.218, 95% CI:0.052-0.915) and a higher incidence rate of intestinal stenosis (OR=16.533, 95% CI:3.824-71.478) were found in UC inpatients with CRC. Conclusions: A long disease course is a risk factor for UC patients developing CRC, while 5-ASA therapy can reduce the risk of suffering from CRC. For UC patients with intestinal stenosis, CRC should be warned for occurring.

Assessment of the Changes in Mitochondrial Gene Polymorphism in Ulcerative Colitis and the Etiology of Ulcerative Colitis-associated Colorectal Cancer

Mitochondria are energy-producing organelles, and dysfunction in these organelles causes various types of disease. Although several studies have identified mutations in nuclear DNA that are associated with the etiology of ulcerative colitis (UC), information regarding mitochondrial DNA (mtDNA) in UC is limited. This study aimed to investigate the mitochondrial DNA polymorphism underlying the etiology of UC and UC-associated colorectal cancer. Next-generation sequencing was performed to assess mitochondrial DNA mutations in 12 patients with UC-associated cancer. The mtDNA mutations in the non-neoplastic mucosa, tumor tissues, and healthy controls were compared. The incidence of mutations of nicotinamide adenine dinucleotide phosphate ubiquinone oxidase subunit, ATP synthetase, and tRNA was higher in non-neoplastic mucosa in those with UC compared with the healthy controls. However, no statistically significant differences were observed in mutations between the tumor tissues and non-neoplastic mucosa in UC. Significant mutations in mtDNA were observed in the non-neoplastic mucosa of patients with UC-associated cancer.

TIMP1 Is A Potential Key Gene Associated With The Pathogenesis And Prognosis Of Ulcerative Colitis-Associated Colorectal Cancer.

PurposeColorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide. As a high-risk factor for CRC, ulcerative colitis (UC) has been demonstrated to lead to epithelial dysplasia, DNA damage, and eventually cancer. There are approximately 18% of patients with UC may develop CRC.Patients and methodsThe gene expression profiles were retrieved from the Gene Expression Omnibus. The Database for Annotation, Visualization and Integrated Discovery was employed to conduct gene annotations. Protein-protein interaction network was constructed by the Search Tool for the Retrieval of Interacting Genes, and further analysed by the Molecular Complex Detection. The correlation between TIMP1 and prognosis was evaluated by the Gene Expression Profiling Interactive Analysis. To predict the potential functions of TIMP1, the GeneMANIA, Coremine, and FunRich were employed. After transfection with small interfering RNA targeting TIMP1, cell proliferation, migration, and apoptosis were determined by CCK-8, scratch wound, and Annexin V-FITC/PI assays, respectively.ResultsTIMP1, consistently overexpressed in the initiation and progression of UC-associated CRC (ucaCRC), was identified to be a potential biomarker for the prognosis of patients with CRC. Experimental results showed knockdown of TIMP1 could increase the migration, while did not affect the proliferation and apoptosis of RKO cells. The role of TIMP1 in the malignant transformation of ucaCRC was confirmed by using the protein/gene interactions and biological process annotation and validated by analysing the transcription factors targeting TIMP1.ConclusionTIMP1 is consistently upregulated in the pathological process of ucaCRC and can be a potential biomarker for the worse prognosis of CRC.

Loss of RUNX3 Immunoreactivity in Non-Neoplastic Rectal Mucosa May Predict the Occurrence of Ulcerative Colitis-Associated Colorectal Cancer

Background/Aims: Runt-related transcription factor (RUNX) 3 is a tumor suppressor whose expression is reduced in non-neoplastic rectal mucosa of patients with ulcerative colitis (UC) with coexisting colitis-associated cancer (CAC). We aimed to evaluate RUNX3 utility as a predictive marker for CAC using immunohistochemistry (IHC) for non-neoplastic UC mucosa. Methods: We retrospectively compared the RUNX3 expression detected by IHC between non-neoplastic rectal biopsy specimens from 20 cases with invasive cancer (CAC group) and 20 cases selected from 138 patients without CAC (non-CAC group) that were treated during the same period (2006–2017) and were matched for sex, duration, extension, and age. We validated the results using tissue microarrays (TMA) of 44 operated cases with CAC. The RUNX3 expression level was determined by calculating the percentage of RUNX3-positive-cells. Results: The RUNX3 expression was lower in the CAC than that in the non-CAC group (35.6 vs. 70.7%, p = 0.03). For a cutoff value of 58%, the sensitivity and specificity for predicting CAC were 75.0 and 70.0% respectively. The immunostaining results for the TMA showed the same trend; 74% of cases with CAC were negative for the RUNX3 expression. Conclusion: RUNX3 immunostaining of non-neoplastic mucosa is useful for identifying UC patients at a high risk of developing CAC.

Surveillance Colonoscopy for Ulcerative Colitis-Associated Colorectal Cancer Offers Better Overall Survival in Real-World Surgically Resected Cases.

To determine the effectiveness of surveillance colonoscopy (SC) and optimize its use by assessing real-world surgically resected cases of ulcerative colitis (UC)-associated colorectal cancer (CRC) and dysplasia. Clinicopathological data of 406 (238 CRC and 168 dysplasia) patients who underwent surgical resection in 10 UC specialized institutions were retrospectively reviewed. The overall survival (OS) rates were compared between the SC and non-SC groups. The incidence of and risk factors for early-onset CRC (<8 years after UC onset) were identified. The distribution of CRC lesions was also assessed. Cancer stages were significantly more advanced in the non-SC group than in the SC group (P < 0.001). The patients in the SC group showed significantly better OS than those in the non-SC group (5-year OS: 89% vs 70%; log-rank test: P = 0.001). Seventeen percent of patients developed CRC within 8 years after UC onset. The age at UC onset was a risk factor and a good predictor of early-onset CRC (<8 years) (P < 0.01; AUC: 0.85). The most common sites of CRC were the rectum (51%) and sigmoid colon (20%). Multiple CRC was identified in 16% of patients. Surveillance colonoscopy was effective and improved the OS in patients with UC. We recommend that patients with late-onset UC (>40 years) undergo SCs earlier because of the high incidence of CRC within 8 years of UC onset. Moreover, the rectum and sigmoid colon should be more thoroughly examined.