Pro-inflammatory Cytokines Promote the Occurrence and Development of Colitis-associated Colorectal Cancer by Inhibiting miR-615-5p.

BACKGROUND: Patients with ulcerative colitis (UC) may be prone to colitis-associated colorectal cancer (CAC), but there is still a poor understanding of the underlying mechanism so far. This study intended to clarify the role of pro-inflammatory cytokines and miR-615-5p in this process. METHODS: This experiment first detected miR-615-5p expressions in paraffin-embedded sections of colonic tissues from patients with UC and CAC. Then, we investigated the mechanism through which pro-inflammatory cytokines affected miR-615-5p. Furthermore, in vivo and in vitro tests were performed to identify how miR-615-5p affected colorectal cancer (CRC). Dual-luciferase reporter assay was then employed to identify the targeting relationship between miR-615-5p and stanniocalcin-1 (STC1). RESULTS: The miR-615-5p was lowly expressed in both cancerous and noncancerous colonic tissues of patients with CAC. Pro-inflammatory cytokines downregulated miR-615-5p expression. Overexpression of miR-615-5p reduced the proliferation and migration of CRC cells and had a certain therapeutic effect on in human CRC xenograft mice. Stanniocalcin-1 was identified to be a target gene of miR-615-5p and was involved in the effect of miR-615-5p on CRC. CONCLUSIONS: During the progression from UC to CAC, pro-inflammatory cytokines downregulate miR-615-5p, which may induce the upregulation of STC1, and promote the occurrence and development of tumors. These findings offer new insights into the mechanism of CAC and may indicate novel tumor markers or therapeutic targets.

Prognostic analysis and nomogram establishment in patients with early esophageal cancer receiving endoscopic therapy: a population-based study.

Background: The growing numbers of early esophageal cancer (EEC) have increased the demand for endoscopic therapy. Objectives: To clarify the influential factors for the prognosis of patients with EEC receiving endoscopic surgery, and to construct a nomogram to evaluate the prognostic value of endoscopic therapy. Design: Prognostic analysis study. Methods: Clinical data of EEC patients who received endoscopic therapy between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results database and used to construct the nomogram. The prognosis was analyzed by R language; the nomogram was constructed by Cox survival analysis; and the accuracy of the nomogram was verified by C index and the receiver operating characteristic (ROC) and calibration curves. X-Tile software was used to stratify the risk of patients. Results: Our study constructed the nomogram of the prognosis of patients with EEC treated by endoscopic surgery, including 1118 patients and 5 independent prognostic factors of esophageal cancer-specific survival. The C index and the area under the ROC curve (AUC) of the training and verification cohorts were all >0.75. The calibration curve also reflected the good consistency of the model in predicting survival. Significant difference in the risk of patients from different stratifications with the same T staging existed, and the model had a better C index than that of the T staging. Conclusion: Our study reports potential influential factors affecting the prognosis of EEC patients who received endoscopic therapy and establishes a reliable nomogram to predict the risk and prognosis, which has certain advantages compared with traditional TNM staging system.

Immunomodulatory Effect of Serum Exosomes From Crohn Disease on Macrophages via Let-7b-5p/TLR4 Signaling.

BACKGROUND: Exosomes are extensively reported to be strongly associated with many immunologic diseases, including Crohn disease (CD). Meanwhile, the dysfunction of macrophage activation has been proposed to be critical for the pathogenesis of CD. However, it is an unsettled issue whether serum exosomes from CD could activate macrophages and participate in its pathogenesis. Our study intended to clarify the role of CD-derived exosomes on macrophages to elucidate a novel mechanism and possible diagnostic and therapeutic strategies. METHODS: Serum exosomes were isolated and identified. Functional assays in vitro were performed on Raw264.7 macrophages, followed by exosomal microRNA (miRNA) profiling and bioinformatics analyses via high-throughput sequencing. In animal experiments, exosomes were intraperitoneally injected into dextran sulfate sodium-induced colitis. RESULTS: In vitro CD-derived exosomes induced proinflammatory cytokine expression and increased macrophage counts. Meanwhile, the intervention of exosomes from CD with epithelial cells led to increased permeability of the intestinal epithelial barrier. In vivo, CD-derived exosomes could circulate into the intestinal mucosa and significantly aggravate colitis. Furthermore, CD changed the miRNA profile of exosomes and further analysis revealed a differential expression of let-7b-5p. Mechanistically, the let-7b-5p/TLR4 pathway was recognized as a potential contributor to macrophage activation and inflammatory response. Furthermore, serum exosome-mediated let-7b-5p mimic delivery alleviated colitis significantly. CONCLUSIONS: Our study indicated that serum exosomes can circulate into the intestinal mucosa to aggravate colitis by regulating macrophage activation and epithelial barrier function. In addition, CD showed altered exosomal miRNA profiles. Furthermore, serum exosome-mediated let-7b-5p-mimic delivery may significantly alleviate colitis, providing potential novel insight into an exosome-based strategy for the diagnosis and treatment of CD.

Multivariate analysis of metastasis­related risk factors for patients with gastroenteropancreatic neuroendocrine tumors based on clinicopathological and endoscopic features.

Gastroenteropancreatic neuroendocrine tumors (GEP­NETs) are relatively uncommon. Unfortunately, epidemiological studies on the incidence of GEP­NETs worldwide have reported a marked increase in the detection of these tumors. Although they often exhibit relatively indolent clinical courses, GEP­NETs have the potential for lethal progression, especially in patients who present with advanced disease. Early detection and surgical removal is currently the only reliable curative treatment for GEP­NET patients. The objective of this study was to analyze the clinicopathological characteristics of GEP­NETs and explore the metastasis­related risk factors of patients with GEP­NETs. One hundred and forty­six patients diagnosed pathologically with GEP­NETs from January 2001 to January 2015 at the Second Xiangya Hospital of Central South University were retrospectively evaluated. We retrieved and analyzed information concerning clinical characteristics and metastasis­related risk factors, and used Chi­square test and logistic regression analysis to analyze the clinicopathological characteristics of GEP­NETs and explore the association between tumor metastasis and possible related risk factors. The results revealed that the most common clinical manifestations were abdominal pain (n=88), alteration in the character of stool (n=58) and melaena (n=33). Rectum (91/146, 62.3%) and stomach (19/146, 13.0%) were the main sites of metastasis. Both Chi­square test and logistic regression analysis showed that tumor size (P<0.05), tumor type (P=0.008) and peritumoral lymphatic vessel density (LVD) (P=0.004) were significantly correlated with tumor metastasis. Neither Chi­square test nor logistic regression analysis indicated that gender (P>0.05), age (P>0.05), tumor location (P>0.05), tumor number (P>0.05), chromaffin granule protein A [chromogranin A (CgA), P>0.05], synaptophysin (Syn, P>0.05) or intratumoral LVD (P>0.05) had a significant correlation with tumor metastasis. Chi­square test revealed that tumor grade was significantly correlated with tumor metastasis. In conclusion, GEP­NETs may occur in multiple sites of the digestive system and lack specific clinical manifestations. Tumor size, tumor type, peritumoral LVD, total LVD and tumor grade are metastasis­related risk factors for GEP­NET patients.