Aspirin Inhibits Carcinogenesis of Intestinal Mucosal Cells in UC Mice Through Inhibiting IL-6/JAK/STAT3 Signaling Pathway and Modulating Apoptosis and Proliferation.

BACKGROUND: Colorectal cancer is related to ulcerative colitis. This study aimed to investigate the effects of aspirin on non-specific inflammation developing into cancer. METHODS: Ulcerative colitis model was generated by administrating azoxymethane/dextran sulfate sodium to mice. Weight, tumor size/ amount, and intestinal mucositis scores were analyzed. Inflammatory cell infiltration and atypical hyperplasia were determined with hematoxylin-eosin staining. Immunohistochemical assay was used to detect the proliferating cell nuclear antigen. Interleukin-6 and interleukin-10 were detected using enzyme-linked immunosorbent assay. Signal transducer and activator of transcription 3, phosphorylated-STAT3, cyclin D1, and suppressor of cytokine signaling 3 were examined with western blotting. RESULTS: Aspirin remarkably decreased tumor size/amount compared to those of the ulcerative colitis model group (P < .05). Interleukin-6 was increased and interleukin-10 was decreased in mice of ulcerative colitis model group compared with the control group (P < .05). Aspirin markedly reduced interleukin-6 and enhanced interleukin-10 compared to the ulcerative colitis model group (P < .05) induced Azoxymethane/dextran sulfate sodium inflammation (3 weeks) and atypical hyperplasia (8 weeks). Aspirin predominantly inhibited the "inflammation-atypical hyperplasia-cancer" process and alleviated inflammatory cell infiltration of mice in the ulcerative colitis model group. Aspirin promoted apoptosis and alleviated proliferating cell nuclear antigen of atypical hyperplastic intestinal mucosal cells at 8 weeks post-modeling. The expression of phosphorylated-STAT3, signal transducer and activator of transcription 3, cyclin D1, and suppressor of cytokine signaling 3 was significantly increased in mice of ulcerative colitis model group compared to the control group (P < .05). Aspirin remarkably decreased phosphorylated-STAT3, signal transducer and activator of transcription, and cyclin D1 expression compared with ulcerative colitis model group (P < .05). CONCLUSION: Aspirin inhibited carcinogenesis of intestinal mucosal cells in the ulcerative colitis model by inhibiting the interleukin-6/ Janus kinase/signal transducer and activator of transcription 3 signaling pathway and promoted apoptosis, thereby suppressing proliferation.

Long non-coding RNA-KCNQ1OT1 mediates miR-423-5p/microfibril-associated protein 2 axis in colon adenocarcinoma.

BACKGROUNDS: Long non-coding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs) that contribute to carcinogenesis. Herein, we plan to explore whether lncRNA KCNQ1OT1 modulated miR-423-5p/microfibril-associated protein 2 (MFAP2) signaling axis is implicated in the progression of human colon adenocarcinoma. MATERIAL AND METHODS: Clinical specimens were collected for histologic examination and gene expression analysis. In vitro experimental measurements, including CCK8, transwell and TUNEL staining, were performed to evaluate cell proliferation, migration and apoptosis. RESULTS: up-regulation of KCNQ1OT1 and MFAP2 and down-regulation of miR-423-5p in COAD tissues were substantiated by The Cancer Genome Atlas (TCGA) database and our clinical specimens. In vitro experimental measurements exhibited that knockdown of KCNQ1OT1 facilitated miR-423-5p expression and inhibited MFAP2 expression, simultaneously. Transfection of si-KCNQ1OT1, miR-423-5p mimics or si-MFAP2 had the ability to repress malignant phenotypes of COAD cells. Intriguingly, overexpression of MFAP2 restrained si-KCNQ1OT1- or miR-423-5p mimics-induced the inhibition of cell proliferation and migration and elevation of the apoptotic proportion of COAD cells. CONCLUSIONS: KCNQ1OT1 serves as a molecular sponge of miR-423-5p to accelerate the expression of MFAP2 that may be involved in the development of COAD. Our findings present a novel signaling axis KCNQ1OT1/miR-423-5p/MFAP2, which provides a theoretical basis and therapeutic target for the treatment of COAD.

Glucagon-like peptide (GLP) -2 improved colonizing bacteria and reduced severity of ulcerative colitis by enhancing the diversity and abundance of intestinal mucosa.

The global incidence of ulcerative colitis (UC) continues to increase while it's clinical cure rate remains low. Intestinal mucosal ulcers have segmental distribution and variable severity. Intestinal bacteria are closely related to intestinal immunity and metabolism; however, the relationship between intestinal microbiome profile and the occurrence of UC, as well as the contribution of glucose metabolism, are not well understood. This was investigated in the present study using mucosal biopsies from patients with UC and healthy control subjects. We performed high throughput 16S rRNA gene sequencing to estimate microbiota composition and abundance as well as their association with clinical indices such as lesion severity. The results showed that the diversity and abundance of intestinal microbiota were significantly lower in patients with UC than in healthy subjects; however, these were unrelated to ulcer severity. Serum glucagon-like peptide 2 (GLP-2) level was associated with reduced microbiota diversity and abundance in UC. These results indicate that colonization by specific microbiota is not the main determinant of pathologic status in UC. Additionally, therapeutic strategies that increase GLP-2 levels in intestinal mucosa may be effective in the treatment of UC.

IL-6/STAT3/SOCS3 signaling pathway playing a regulatory role in ulcerative colitis carcinogenesis.

OBJECTIVE: Large-scale clinical studies have shown that ulcerative colities were related with colorectal cancer. In this study, animal model was established by AOM/DSS method to explore the activation of IL-6-STAT3-SOCS3 signaling pathway and the expression of pathway-related proteins in ulcerative colitis carcinogenesis, in order to lay a foundation for exploring the regulation mechanism of IL-6/STAT3/SOCS3 signaling pathway in ulcerative colitis carcinogenesis. METHOD: AOM/DSS modeling method was used to establish animal models of ulcerative colitis carcinogenesis; colonic mucosa specimens were collected at different time points for pathological examination. Immunohistochemical method and western blot were used to detect the expression of IL6, STAT3 and SOCS3 protein in the control group, UC model + empty vector group and UC model + STAT3 knockout group. RESULTS: In UC model + empty vector group, IL6 and STAT3 expression was increased as lesion degree increased (P < 0.05). The expression of SOCS3 was weakened and the degree of activation decreased (P < 0.05). IL6 expression increased in UC model + STAT3 knockout group (P < 0.05) while the expression of SOCS3 decreased; compared with the UC model + empty vector group, there was a significant difference (P < 0.05). CONCLUSION: The expression and activation of IL6 and STAT3 expression were enhanced in ulcerative colitis carcinogenesis, and their expression increased with the lesion degree increased, reflecting the disease progression to a certain extent. The expression and activation of SOCS3 expression decreased. STAT3 had a certain effect on the expression of SOCS3, playing a certain regulatory role in ulcerative colitis carcinogenesis.