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

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          Ulcerative 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.


          Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to induce UC-CRC in C57BL/6 mice. AOM/DSS-induced mice were treated with 5×10 8 pfu miR-370-3p overexpressing-adenovirus via tail-vein injection every two weeks.


          We 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.


          Taken 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.

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          Most cited references 39

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            MicroRNAs in cancer: small molecules with a huge impact.

             Carlo Croce,  V Iorio (2009)
            Every cellular process is likely to be regulated by microRNAs, and an aberrant microRNA expression signature is a hallmark of several diseases, including cancer. MicroRNA expression profiling has indeed provided evidence of the association of these tiny molecules with tumor development and progression. An increasing number of studies have then demonstrated that microRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. Here we review our current knowledge about the involvement of microRNAs in cancer and their potential as diagnostic, prognostic, and therapeutic tools.
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              Cancer risk in patients with inflammatory bowel disease: a population-based study.

              The objective of the current study was to determine the incidence of cancer among persons with inflammatory bowel disease (IBD) and to compare these incidence rates with those of the non-IBD population using population-based data from the administrative claims data of Manitoba's universal provincial insurance plan (Manitoba Health). IBD patients were matched 1:10 to randomly selected members of the population without IBD based on year, age, gender, and postal area of residence. The incidence of cancer was determined by linking records from the IBD and non-IBD cohorts with the comprehensive Cancer Care Manitoba registry. Incidence rates and rate ratios (IRR) were calculated based on person-years of follow-up (Crohn's disease = 21,340 person-years and ulcerative colitis [UC] = 19,665 person-years) for 1984-1997. There was an increased IRR of colon carcinoma for both Crohn disease patients (2.64; 95% confidence interval [95% CI], 1.69-4.12) and UC patients (2.75; 95% CI, 1.91-3.97). There was an increased IRR of rectal carcinoma only among patients with UC (1.90; 95% CI, 1.05-3.43) and an increased IRR of carcinoma of the small intestine only in Crohn disease patients (17.4; 95% CI, 4.16-72.9). An increased IRR of extraintestinal tumors was observed only for the liver and biliary tract in both Crohn disease patients (5.22; 95% CI, 0.96-28.5) and UC patients (3.96; 95% CI, 1.05-14.9). There was an increased IRR of lymphoma for males with Crohn disease only (3.63; 95% CI, 1.53-8.62), and this finding did not appear to be related to use of immunomodulatory therapy. Compared with controls, Crohn's disease was associated with an increased risk of cancer overall, but UC was not. There appear to be similar increased risks for developing colon carcinoma and hepatobiliary carcinoma among patients with Crohn disease and UC. There is an increased risk of developing rectal carcinoma in UC patients, an increased risk of developing carcinoma of the small bowel in Crohn disease patients, and an increased risk of developing lymphoma among males with Crohn disease. Copyright 2001 American Cancer Society.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                13 March 2020
                : 14
                : 1127-1141
                [1 ]Department of Gastroenterology and Hepatology, Shengjing Hospital of China Medical University , Shenyang 110004, People’s Republic of China
                [2 ]Department of Gastroenterology, The Second Affiliated Hospital of Shenyang Medical College , Shenyang 110035, People’s Republic of China
                Author notes
                Correspondence: Yan Lin Department of Gastroenterology and Hepatology, Shengjing Hospital of China Medical University , 36 Sanhao Street, Shenyang110004, People’s Republic of China Tel/Fax +86-24-96615-26211 Email lin_yan02@sina.com
                © 2020 Lin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, Tables: 1, References: 52, Pages: 15
                Original Research


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