LCN2 as a Potential Diagnostic Biomarker for Ulcerative Colitis-Associated Carcinogenesis Related to Disease Duration

BackgroundPatients with long-duration ulcerative colitis (UC) had a higher risk of developing ulcerative colitis-associated carcinogenesis (UCAC) when compared to those with short-duration UC. This study aimed to discover the biomarker for cancer surveillance related to disease duration.MethodsThe microarrays were divided into short-duration (<10 years) UC, long-duration (≥10 years) UC, UCAC, and normal groups in the Gene Expression Omnibus (GEO) datasets. Differentially expressed genes (DEGs) of GEO and the hub genes of the selected weighted gene co-expression network analysis (WGCNA) were intersected to obtain the overlapping genes. Among these genes, the key gene was identified by using the protein–protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the cytoHubba of Cytoscape, and the expression levels. Also, immunofluorescence of human colonic mucosa and animal experiment were used to validate the expression trend of the key gene in the progress of UC developing into UCAC.ResultsLipocalin-2 (LCN2) was more relevant with disease duration of UC and significantly negatively correlated with the risk of UCAC. The expression level of LCN2 in short-duration UC was higher than that of long-duration UC (P < 0.01), long-duration UC was higher than that of UCAC (P = 0.001), and UC and UCAC were all higher than that of the normal (P < 0.001). We then discovered that the expression trend of LCN2 in blood and stool samples was consistent with that in colorectal mucosa.ConclusionThe research indicates that LCN2 could be a novel biomarker to evaluate cancer surveillance related to disease duration of developing UC into UCAC. Compared with that of blood samples, stool detection of LCN2 may have more advantages for diagnosis value of early stage of UCAC as a complement to colonoscopy surveillance.

Multiple Colorectal Mucosa-Associated Lymphoid Tissue Lymphoma Successfully Treated with Chemotherapy

The standard treatment for colorectal mucosa-associated lymphoid tissue (MALT) lymphoma has not yet been established due to the rarity of the disease. Here, we report a case of long-term response to chemotherapy for colorectal MALT lymphoma (stage I). A 77-year-old frail female patient with diabetes mellitus and dementia developed melena of unknown etiology, and a colonoscopy was performed at a nearby hospital. A biopsy suggested malignant lymphoma, and she was referred to our department. As a result of re-examination of colonoscopy, a total of 3 submucosal tumor-like lesions were confirmed. Of these, a biopsy of the lesions in the ascending colon and rectum was performed, and MALT lymphoma was diagnosed on the basis of the histopathological findings. Following close examination, no other lymphoma lesions were found, and the patient was diagnosed with primary colorectal MALT lymphoma, stage I. After 1 course of R-THP-COP chemotherapy (rituximab + cyclophosphamide, pirarubicin, vincristine, and prednisone), the rectal lesion was confirmed to have almost disappeared endoscopically, and lymphoma cells were not found histopathologically. The patient was determined to be in complete remission (CR). However, due to hematological toxicity and a slight worsening of glucose control, the second chemotherapy course was changed to the BR regimen (rituximab + bendamustine), and 4 courses were performed (5 total courses of chemotherapy). Currently, >3 years have passed since reaching CR, and the patient is alive without recurrence.

Motiro: a unified automatic framework for statistical analysis of probe-based confocal laser endomicroscopy videos of colorectal mucosa

Probe-based Confocal Laser Endomicrocopy (pCLE) enables imaging the colorectal mucosa for screening and surveillance of cancer. Analyzing acquired videos relies on subjectivity of the endomicroscopists. Quantitative criteria are needed to enhance the diagnostics obtained using pCLE. We present Motiro, an automatic framework to extract features of the colorectal mucosa imaged by pCLE. Morphometric features of the crypts of the healthy colorectal mucosa are analysed and their variability quantified using the Shannon entropy. Hellinger distance compares the statistics of a morphometric parameter in multiple mucosas (or mucosas' regions). Quantification of variability of the healthy mucosa is a prerequisite for pCLE-based early diagnostics of colorectal cancer.

Relationship between Metalloprotease-7 and -14 and Tissue Inhibitor of Metalloprotease 1 Expression by Mucosal Stromal Cells and Colorectal Cancer Development in Inflammatory Bowel Disease

Colorectal carcinoma (CRC) associated with inflammatory bowel disease (IBD) is an example of an inflammation-related cancer. Matrix metalloproteases (MMP) are known to be associated with both processes. The aim of the study was to compare the expression of MMP-7, MMP-14 and tissue inhibitor of metalloproteases-1 (TIMP-1) in sporadic CRC- and IBD-associated CRC, and to compare the expression in inflamed and non-inflamed colonic tissue samples from IBD patients without or with associated CRC. An immunohistochemical study of MMP-7, -14 and TIMP-1 was performed on sporadic CRC (n = 86), IBD-associated CRC (n = 23) and colorectal mucosa of non-tumor samples from IBD patients without (n = 47) and with (n = 23) associated CRC. These factors were more frequently expressed by cancer-associated fibroblasts (CAF) from IBD-associated CRC than by CAF from CRC not associated with IBD. Regarding the inflamed tissue of IBD patients, Crohn’s disease (CD) patients with CRC development showed a higher expression of MMP-14 by fibroblasts and by mononuclear inflammatory cells (MICs) than CD patients without CRC development. In non-inflamed tissue samples, MMP-7 associated with fibroblasts and MICs, and TIMP-1 associated with MICs, were more frequently expressed in CD patients with CRC development than in CD patients without CRC development. Our data suggest that these factor expressions by stromal cells may be biological markers of CRC development risk in IBD patients.

Wnt7a Promotes the Occurrence and Development of Colorectal Adenocarcinoma

ObjectiveThe expression of Wnt7a in colorectal cancer tissues and cell lines was analyzed, and the effect of Wnt7a on the proliferation of colorectal cancer cells was studied, so as to confirm the relationship between Wnt7a and the occurrence and development of colorectal cancer.Methods(1) Immunohistochemical method was used to compare the expression of Wnt7a in different tissues and its relationship with the clinicopathology of colorectal adenocarcinoma. (2) The expression levels of Wnt7a in colorectal cancer cell lines HT-29 and HCT 116 were detected by qRT-PCR. (3) The down-regulated Wnt7A expression vector was constructed, and the down-regulated Wnt7A expression cell line was established. The regeneration ability of cancer cells was detected by stem cell ball formation assay, and the influence of plate cloning assay on the proliferation ability of colorectal cancer cells was detected.Results(1) The positive rates of Wnt7a in normal colorectal mucosa, colorectal adenoma and colorectal adenocarcinoma tissues gradually increased,Wnt7a are closely related to the degree of colorectal adenocarcinoma differentiation, lymph node metastasis and Duke stage. (2) The expression level of Wnt7a in colorectal cancer cells was higher than that in normal colorectal epithelial cells. (3) The down-regulation of Wnt7A reduced the proliferation ability of colorectal cancer cells.ConclusionsWnt7a promotes the occurrence and development of colorectal adenocarcinoma.

Case Report: Two Infant Cases of Langerhans Cell Histiocytosis Involving the Digestive Tract

Langerhans cell histiocytosis (LCH) is a rare disease with uncertain etiology. Langerhans cell histiocytosis with involvement of the gastrointestinal tract is rare and is typically identified in pediatric patients with systemic disease. The present study reports two infantile cases of LCH who initially presented with diarrhea, hematochezia, and rash and were histologically missed on the original examination of the colonic biopsy sections. The diagnosis of LCH was later verified through immunohistochemistry. By combining our experience and previous reports, the multiple hemorrhagic spots of the colorectal mucosa and narrowness and erosion of the distal duodenum might be suggestive manifestations of gastrointestinal involvement in LCH on endoscopic examination. This might be helpful for the early recognition of the disease.

Expression of apoptosis repressor with caspase recruitment domain (ARC) in familial adenomatous polyposis (FAP) adenomas and its correlation with DNA mismatch repair proteins, p53, Bcl-2, COX-2 and beta-catenin

Background Colorectal familial adenomatous polyposis (FAP) adenomas exhibit a uniform pathogenetic basis caused by a germline mutation in the adenomatous polyposis gene (APC), but the molecular changes leading to their development are incompletely understood. However, dysregulated apoptosis is known to substantially affect the development of colonic adenomas. One of the key regulatory proteins involved in apoptosis is apoptosis repressor with caspase recruitment domain (ARC). Methods The expression of nuclear and cytoplasmic ARC in 212 adenomas from 80 patients was analyzed by immunohistochemistry. We also compared expression levels of ARC with the expression levels of p53, Bcl-2, COX-2, and MMR proteins. Statistical analyses were performed by Spearman’s rank correlation and linear regression test. Results ARC was overexpressed in the nuclei and cytoplasm of most FAP adenomas investigated. Cytoplasmic ARC staining was moderately stronger (score 2) in 49.1% (n = 104/212) and substantially stronger (score 3) in 32.5% (n = 69/212) of adenomas compared to non-tumorous colorectal mucosa. In 18.4% (n = 39/212) of adenomas, cytoplasmic ARC staining was equivalent to that in non-tumorous mucosa. Nuclear expression of ARC in over 75% of cells was present in 30.7% (n = 65/212) of investigated adenomas, and nuclear expression in 10–75% of cells was detected in 62.7% (n = 133/212). ARC expression in under 10% of nuclei was found in 6.6% (n = 14/212) of adenomas. The correlation between nuclear ARC expression and cytoplasmic ARC expression was highly significant (p = 0.001). Moreover, nuclear ARC expression correlated positively with overexpression of Bcl-2, COX-2 p53 and β-catenin. Cytoplasmic ARC also correlated with overexpression of Bcl-2. Sporadic MMR deficiency was detected in very few FAP adenomas and showed no correlation with nuclear or cytoplasmic ARC. Conclusions Our results demonstrated that both cytoplasmic and nuclear ARC are overexpressed in FAP adenomas, thus in a homogenous collective. The highly significant correlation between nuclear ARC and nuclear β-catenin suggested that ARC might be regulated by β-catenin in FAP adenomas. Because of its further correlations with p53, Bcl-2, and COX-2, nuclear ARC might play a substantial role not only in carcinomas but also in precursor lesions.