UC-associated Colorectal Cancer Research Articles

P53 terminates the regenerative fetal-like state after colitis-associated injury.

Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated 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.

Potential carcinogenic role of Reg IV in ulcerative colitis-associated colorectal neoplasia.

Early detection of ulcerative colitis-associated neoplasia (UC-N) remains a clinical challenge. Identification of molecular biomarkers for colorectal dysplasia and cancer may be extremely beneficial in early detection and managing cancer risk in long-standing ulcerative colitis (UC) patients. The aim of this work is to investigate the role of Reg IV in comparison to P53 and KRAS in UC-associated dysplasia and colorectal cancer (CRC) in order to evaluate the potential use of Reg IV for dysplasia and cancer screening in UC patients. The study was conducted on 5 groups each 20 colonic endoscopic samples: 1) Normal colonic mucosa, 2) Active UC without dysplasia/carcinoma, 3) UC-associated dysplasia, 4) UC-associated CRC (UC-CRC), 5) Sporadic CRC. All included cases were subjected to Reg IV mRNA expression analysis by quantitative reverse transcription polymerase chain reaction, and immunostaining for Reg IV, P53 and KRAS. Reg IV mRNA expression levels were found to be significantly higher in groups 3 and 4 (mean: 3.37 and 5.70, respectively). Reg IV immunostaining was highly expressed in groups 3 and 4 (mean: 45.80 and 62.35, respectively). While P53 and KRAS immunostaining was highly expressed in group 5 (mean: 64.57 and 62.90). Furthermore, Reg IV immunoexpression had shown a negative correlation with P53 and KRAS immunoexpression in groups 4 and 5. Higher expression of Reg IV in patients with UC-dysplasia and UC-CRC versus KRAS and P53 expression in sporadic CRC, suggests a potential role of Reg IV in UC carcinogenesis pathway. This could advocate the use of Reg IV as a screening biomarker for UC-N among patients with long-standing UC as well as a promising targeted therapeutic strategy.

Establishment of Coloproctitis Cancer Model in Mice and Evaluation of Therapeutic Effect of Chinese Medicine.

Colorectal cancer (CRC) is a common malignancy of the digestive system and has become the third most common malignancy worldwide and the second leading cause of malignancy-related death. Ulcerative coloproctitis (UC) is a precancerous lesion, and UC-associated CRC (UC-CRC) is the most common subtype of CRC. Therefore, a reasonable UC-CRC model is the cornerstone and guarantee of new drug development. Traditional Chinese medicine (TCM) has been widely used in the treatment of UC-CRC due to its good efficacy. As a classic tonic prescription of TCM, Liujunzi decoction (LJZD) has been widely used in the treatment of UC-CRC. In this study, a UC-CRC model was established by combining azomethane and dextran sulfate sodium, and the LJZD was administered. The data confirmed that LJZD can effectively inhibit cancer transition in UC-CRC by using mouse body weight, colorectal length, pathological and inflammatory factors, colorectal barrier function, and cancer markers. This protocol provides a system for evaluating the efficacy of TCM in the prevention and treatment of UC-CRC.

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.

Endoscopic Surveillance for Colorectal Cancer in Pediatric Ulcerative Colitis: A Survey Among Dutch Pediatric Gastroenterologists.

This study aimed to evaluate the current clinical practice of Dutch pediatric gastroenterologists regarding the surveillance for colorectal dysplasia and cancer in pediatric ulcerative colitis (UC), including adherence to guidelines, the initiation and interval of surveillance and applied endoscopy techniques. A clinical vignette-based survey was distributed among all 47 pediatric gastroenterologists who are registered and working in the Netherlands. Thirty-three pediatric gastroenterologists treating children with UC, completed the questionnaire (response rate 70%). Of these respondents, 23 (70%) do conduct endoscopic surveillance in their UC patients. Adherence to any of the available guidelines was reported by 82% of respondents. Twenty-four of 31 respondents (77%) indicated the need for development of a new guideline. Profound variation was witnessed concerning the initiation and interval of surveillance, and risk factors taken into consideration, such as disease extent and concomitant diagnosis of primary sclerosing cholangitis (PSC). The available national and European guidelines recommend the use of chromoendoscopy in the performance of surveillance. This technique was conducted by 8% of respondents, whereas 50% conducted conventional endoscopy with random biopsies. The heterogeneity in surveillance practices underlines the need for consistency among the guidelines, explicitly stated by 77% of the respondents. For this, future research on surveillance in pediatric UC is warranted, focusing on the risk of UC-associated colorectal cancer related to risk factors and optimal endoscopy techniques.

Elective and Emergent Surgery in the Ulcerative Colitis Patient.

Ulcerative colitis (UC) requires surgical management in 20 to 30% of patients. Indications for surgery include medically refractory disease, dysplasia, cancer, and other complications of UC. Appropriate patient selection for timing and staging of surgery is paramount for optimal outcomes. Restorative proctocolectomy is the preferred standard of care and can afford many patients with excellent quality of life. There have been significant shifts in the treatment of UC-associated dysplasia, with less patients requiring surgery and more entering surveillance programs. There is ongoing controversy surrounding the management of UC-associated colorectal cancer and the techniques that should be used. This article reviews the most recent literature on the indications for elective and emergent surgical intervention for UC and the considerations behind the surgical options.

Changes in Lysophospholipid Components in Ulcerative Colitis and Colitis-associated Cancer.

In recent years, it has become clear that, in addition to normal cytokines, phospholipid mediators play an important role in the development, growth, infiltration, and metastasis of cancer and in the cancer microenvironment. A phospholipid analysis method using tandem mass spectrometry (LC-MS/MS) with high detection sensitivity has enabled quantification of phospholipids, even when using a very small sample. To date, we had applied this MS technology to colorectal cancer tissue. Therefore, in this study, this mass spectrometry technique was applied to ulcerative colitis (UC) and UC-related colorectal cancer, and an analysis was conducted with the aim of clarifying which lysophospholipids specifically change in each type of tissue. UC-associated colorectal cancer tissue and UC mucosa were collected from surgical specimens of colitic cancer (n=3). Cancerous and non-cancerous tissues were collected from surgical specimens from patients with sporadic colorectal cancer (n=11). After extraction from these tissues, the amounts of lysophospholipids were quantified by LC-MS/MS. In addition, lysophosphatidylserine (LPS) and lysophosphatidylinositol (LPI) were quantified for each molecular species of fatty acids. Compared to normal mucosa, LPI was increased 3.8-fold (p<0.001) and LPS 3.5-fold (p<0.001) in UC-related colorectal cancer. Molecular species of LPI which were increased in UC-related colorectal cancer were 18:0 (p=0.001), 16:0 (p=0.03) and 20:4 (p=0.004), and of LPS were 18:0 (p<0.001) and 22:6 (p=0.014). Lysophospholipids increased in colorectal cancer and in UC-associated colorectal cancer. In particular, LPI may have contributed significantly to colitis-associated carcinogenesis.

Differentially Deregulated MicroRNAs as Novel Biomarkers for Neoplastic Progression in Ulcerative Colitis.

Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs (miRNA) are epigenetic regulators that have been involved in the development of UC-associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied. In this study, we analyzed the expression of 96 preselected miRNAs in human formalin-fixed and paraffin-embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia, and 12 UC-associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas, and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual quantitative real-time polymerase chain reaction in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC-associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs). Sixty-four miRNAs were found to be differentially deregulated in the UC-associated CRC sequence. Eight of these miRNAs were chosen for further validation. We confirmed miR-31, -106a, and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC-associated CRC sequence (all P < 0.01). Notably, these miRNAs also confirmed to have a significant differential expression compared with sporadic CRC (all P < 0.05). UC-associated and sporadic CRCs have distinct miRNA expression patterns, and some miRNAs indicate early neoplastic progression.

Identification of Significant Modules and Targets of Xian-Lian-Jie-Du Decoction Based on the Analysis of Transcriptomics, Proteomics and Single-Cell Transcriptomics in Colorectal Tumor.

PurposeColorectal cancer (CRC) remains the third most common tumor worldwide. Ulcerative colitis (UC) could cause chronic inflammation and ulcers in the colon and rectum. UC is a risk factor for a high incidence of CRC, and the incidence of UC-associated CRC (UC-CRC) is still increasing. Chinese medicine prescription, Xian-Lian-Jie-Du decoction (XLJDD), has been proven its efficacy in some UC-CRC patients. However, the mechanism of XLJDD in treating UC-CRC remains unknown. This study aimed to investigate the mechanism of XLJDD in treating UC-CRC.MethodsWe constructed an AOM/DSS mouse model that could simulate the various stages of UC-CRC in humans. XLJDD and its 5 main components are used to treat the AOM/DSS model, respectively. With the power of high-throughput sequencing technology, we described the mechanism of XLJDD from transcriptomics, proteomics, and single-cell transcriptomics.ResultsOur results showed that XLJDD could effectively suppress the occurrence and development of colorectal tumors. Using the weighted correlation network analysis (WGCNA), several mRNA and protein modules that respond to XLJDD have been identified. Moreover, two essential genes, Mfsd2a and Ccdc85c, were caught our attention. They were prognostic markers in CRC patients, and their expression could be significantly modulated by XLJDD, showing their potential as effective targets of XLJDD. In addition, we also discovered that XLJDD could affect the cell composition of the colorectal tumor environment, especially in the infiltration of B cells.ConclusionWe demonstrated that XLJDD could prevent the initiation and development of colorectal tumors by modulating the expression of Mfsd2a and Ccdc85c and reducing the infiltration of B cells in the tumor microenvironment of colorectal tumor.

Molecular characterization of dysplasia-initiated colorectal cancer with assessing matched tumor and dysplasia samples.

PurposeUlcerative colitis (UC) is known to have an association with the increased risk of colorectal cancer (CRC), and UC-associated CRC does not follow the typical progress pattern of adenoma-carcinoma. The aim of this study is to investigate molecular characteristics of UC-associated CRC and further our understanding of the association between UC and CRC.MethodsFrom 5 patients with UC-associated CRC, matched normal, dysplasia, and tumor specimens were obtained from formalin-fixed paraffin-embedded (FFPE) samples for analysis. Genomic DNA was extracted and whole exome sequencing was conducted to identify somatic variations in dysplasia and tumor samples. Statistical analysis was performed to identify somatic variations with significantly higher frequencies in dysplasia-initiated tumors, and their relevant functions were investigated.ResultsTotal of 104 tumor mutation genes were identified with higher mutation frequencies in dysplasia-initiated tumors. Four of the 5 dysplasia-initiated tumors (80.0%) have TP53 mutations with frequent stop-gain mutations that were originated from matched dysplasia. APC and KRAS are known to be frequently mutated in general CRC, while none of the 5 patients have APC or KRAS mutation in their dysplasia and tumor samples. Glycoproteins including mucins were also frequently mutated in dysplasia-initiated tumors.ConclusionUC-associated CRC tumors have distinct mutational characteristics compared to typical adenoma-carcinoma tumors and may have different cancer-driving molecular mechanisms that are initiated from earlier dysplasia status.

Research progress on the carcinogenesis mechanism of inflammation in ulcerative colitis: a narrative review.

In this review, we have summarized the influence of inflammation-related pathological mechanisms on the development of ulcerative colitis (UC) to colorectal cancer (CRC). UC is a chronic inflammatory bowel disease (IBD) of unknown etiology that affects the colon and rectum. Long-term inflammation of UC may greatly increase the risk of CRC, and the secretion of inflammatory factors and sustained inflammation may be key drivers of UC-associated CRC progression. Compared with the general population, the risk of CRC in patients with UC is 2.4 times higher, and the mortality rate of patients with UC is higher than that of those with sporadic CRC. The use of non-steroidal anti-inflammatory drugs can reduce the probability of UC transforming into CRC. Literatures about inflammation and UC were extensively reviewed to analyze and discuss. We believe that the mechanism of continuous inflammation that promotes cancer in UC may be the result of the mutual influence of intestinal microbes, inflammatory signals, and tissue remodeling. The invasion of intestinal microorganisms activates inflammatory signals and promotes the secretion of inflammatory factors which intensifies the remodeling of the extracellular matrix (ECM) and recruits immune cells. Eventually, a mutually engendering circuit of microbial invasion, release of inflammatory mediators, and remodeling of ECM is formed, which triggers continuous inflammation and promotes development of CRC.

PHLDA1 expression in ulcerative colitis: A potential role in the management of dysplasia.

Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a protein involved in cell proliferation, adhesion and migration in colon cancer. In normal large intestinal mucosa, this protein is expressed only in the crypts. By contrast, its expression in adenomas and cancers of the large intestine is spread throughout the glandular ducts, and it has been reported that PHLDA1 may be involved in the process of carcinogenesis. PHLDA1 may also be involved in the pathogenesis of ulcerative colitis (UC). The expression levels of PHLDA1 in tissues from patients with UC were analyzed using immunohistochemistry, and its relationship with the development of UC-associated colorectal cancer (UC-CRC) was examined. Overall, tissue samples from 143 lesions (90 colitis lesions, 39 dysplastic lesions and 14 UC-CRC lesions) were prepared from excised specimens of 49 patients with UC who underwent surgery in Tokyo Medical and Dental University Hospital between January 2004 and December 2017. Subsequently, immunostaining for PHLDA1 was performed. PHLDA1 expression was evaluated in UC-CRC and dysplastic tissues within the entire lesion area on the slide and in colitis over the area of the accompanying duct. The cytoplasmic staining intensity was classified into four levels, and the expression score (0-2 points) was calculated. The median PHLDA1 expression score was 0.295 for colitis, 0.607 for dysplasia and 0.865 for UC-CRC. The dysplasia expression score was significantly higher than the colitis score (P<0.001), while the UC-CRC expression score was significantly higher than the dysplasia score (P=0.003). The expression levels of PHLDA1 in UC cases were higher in colitis, followed by dysplasia and UC-CRC, which suggested that this protein may be involved in the carcinogenesis of UC-CRC. In addition, PHLDA1 immunostaining may help in the diagnosis of dysplasia, which is a type of precancerous lesion.

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.

MiR-370-3p Alleviates Ulcerative Colitis-Related Colorectal Cancer in Mice Through Inhibiting the Inflammatory Response and Epithelial-Mesenchymal Transition.

IntroductionUlcerative colitis (UC) is a chronic and inflammatory bowel disease. UC-associated colorectal cancer (UC-CRC) is one of the most severe complications of long-standing UC. In the present study, we explored the effects of miR-370-3p on UC-CRC in vivo and investigated its underlying mechanisms in vivo and in vitro.MethodsAzoxymethane (AOM) and dextran sodium sulfate (DSS) were used to induce UC-CRC in C57BL/6 mice. AOM/DSS-induced mice were treated with 5×108 pfu miR-370-3p overexpressing-adenovirus via tail-vein injection every two weeks.ResultsWe found that miR-370-3p significantly improved the body weights and survival rates and inhibited the tumorigenesis of UC-CRC in AOM/DSS mice. Mechanically, miR-370-3p inhibited AOM/DSS-induced inflammatory response by decreasing tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) through targeting toll-like receptor 4 (TLR4), as demonstrated by down-regulation of TLR4, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and phosphorylated epidermal growth factor receptor (pEGFR). miR-370-3p decreased the expression of tumor-associated proteins, including p53, β-catenin, and ki67 in AOM/DSS-treated mice. Additionally, miR-370-3p remarkably inhibited epithelial-mesenchymal transition (EMT) via increasing E-cadherin expression and reducing N-cadherin and Vimentin expression in vivo. Further studies showed that miR-370-3p repressed proliferation and EMT of colon cancer cells in vitro. Moreover, we proved that miR-370-3p decreased the expression of tumor-associated proteins and reversed EMT by regulating β-catenin in colon cancer cells.ConclusionTaken together, miR-370-3p alleviated UC-CRC by inhibiting the inflammatory response and EMT in mice, which suggested miR-370-3p as a novel potential target for UC-CRC therapy.

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.

Clinical Significance of Aberrantly Methylated OPLAH in Ulcerative Colitis

Background: Chronic inflammation promotes aging and carcinogenesis in colorectal mucosa, particularly in ulcerative colitis (UC); providing a rationale for the development of these molecular alterations as useful biomarkers for diagnosis and risk prediction of UC-associated colorectal cancer (UC-CRC) and sporadic colorectal cancer (S-CRC). Methods: We performed array-based methylation analyses using tissues from 76 patients with S-CRC (vs. normal mucosa) and UC-CRC (vs. UC). In the evaluation phase, 945 colorectal specimens from 352 patients with S-CRC, 31 with UC-CRC, and 57 with UC, were analyzed for methylation levels of identified genes by quantitative pyrosequencing. In the validation phase, 199 non-cancerous rectal mucosa specimens from 20 patients with S-CRC, 61 with UC-CRC, 90 with UC, and 28 healthy volunteers were examined. Findings: Comprehensive analysis identified OPLAH as a hypermethylated CpG site in S-CRC and UC-CRC patients. In the evaluation phase, OPLAH methylation (met-OPLAH) differentiated S-CRC tissue from normal mucosa (area under the receiver operating characteristic curve (AUC):0.95, sensitivity:0.89, specificity:0.95), and met-OPLAH levels in normal mucosa were positively correlated with age. However, met-OPLAH was specifically hypermethylated in UC-CRC tissues and differentiated UC-CRC from UC mucosa (AUC:0.95, sensitivity:0.88, specificity:0.94). Levels of met-OPLAH were significantly higher in rectal tissues vs. proximal mucosa, and were associated with age and disease duration in rectal mucosa. In non-cancerous rectal mucosa, met-OPLAH could discriminate UC patients with or without UC-CRC (AUC:0.84, sensitivity:0.83, specificity:0.72). We further developed ∆met-OPLAH, which could distinguish S-CRC from UC-CRC (P=0.0002, AUC:0.81, sensitivity:0.92, specificity:0.65). Interpretation: Assessment of met-OPLAH can be used for screening of UC-CRC using non-cancerous rectal mucosa, diagnosis using cancerous tissues, and decision-making of surgical approaches using both tissue types in patients with UC and cancer. Funding: Grants in Aid for Scientific Research (17K10628, 18K08591) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. Declaration of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors have no conflict of interests to disclose. Ethical Approval Statement: Specimen collection and experiments were approved by the Institutional Review Boards of all participating institutions. All participants provided a written informed consent for participation in research.

Risk of Colorectal Cancer in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis.

Background Ulcerative colitis (UC) patients have an increased risk for the development of colorectal cancer (CRC). Our aim was to assess the risk of CRC in UC patients compared with disease extent, disease duration, and geographic variation. Methods In this systematic review and meta-analysis, we searched PubMed, scientific meetings, and the bibliographies of identified articles, with English language restrictions for studies published from 1988 to 2018, and assessed the risk of CRC in UC patients. Patients with Crohn's disease, family history of CRC, and colorectal adenomatous polyp (CAP) were excluded from this research. The study was registered with PROSPERO, number CRD42018102213. Findings We included 58 studies that included 267566 UC patients. Extensive UC and left-sided UC had a higher risk of CRC than proctitis UC. Geography also played a role in UC-associated CRC development. The time of malignant transformation in Asian UC patients started after 10-20 years of this disease duration. North American UC-associated CRC patients significantly increased in more than 30 years of this disease duration. Conclusion In a systematic review of the literature, we found that disease extent, disease duration, and geography were strong, independent risk factors in UC-associated CRC development.

MicroRNA-9 methylation reflect epigenetic drift and identify patients with risk for C-associated colorectal neoplasia

Abstract Background MicroRNA(miR)-9 is hypermethylated in age- and cancer-dependent manner. Herein, we hypothesized that miR-9 hypermethylation in normal, aging colorectal epithelium may be an early event in UC-associated colorectal cancer(UC-CRC), leading us to undertake systematic and comprehensive study. Methods A total of 387 colorectal epithelial specimens, including 362 non-neoplastic and 25 neoplastic tissues that were obtained from 238 UC patients, from two different cohorts. Using quantitative bisulfite pyrosequencing, this study design included three-step analysis for the clinical evaluation phase to determine whether miR-9 exhibited age-, location-, or tissue-dependent methylation patterns in multiple mucosal tissues collected from different segments of the colorectum(cecum, transverse, and rectum) in large cohort UC patients. The subsequent external validation phase confirmed our observation that aberrant methylation of miR-9 in non-neoplastic rectal mucosa from UC patients could identify patients with risk for UC-CRC. Results MiR-9 methylation showed a stepwise increase from cecum to rectum in UC patients(P Conclusions MiR-9 methylation in rectal biopsies might be used as a biomarker for identifying patients at high risk for UC-CRC.

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.