文献类型： 外文期刊

作者： Tian, Yuhua ¹ ; Xu, Jiuzhi ¹ ; Li, Yuan ² ; Zhao, Ran ¹ ; Du, Sujuan ¹ ; Lv, Cong ¹ ; Wu, Wei ⁵ ; Liu, Ruiqi ¹ ; Sheng, Xiao ¹ ;

作者机构： 1.China Agr Univ, State Key Labs Agrobiotechnol, Yuanmingyuan West Rd 2, Beijing 100193, Peoples R China

2.China Agr Univ, Beijing Adv Innovat Ctr Food Nutr & Human Hlth, Yuanmingyuan West Rd 2, Beijing 100193, Peoples R China

3.China Agr Univ, Coll Biol Sci, Yuanmingyuan West Rd 2, Beijing 100193, Peoples R China

4.China Agr Univ, Coll Food Sci & Nutr Engn, Beijing, Peoples R China

5.Tongji Univ, Dept Gastroenterol, Shanghai Peoples Hosp 10, Shanghai 200072, Peoples R China

6.Capital Med Univ, Sch Pharmaceut Sci, Beijing, Peoples R China

7.Imperial Coll London, Inst Reprod & Dev Biol, Fac Med, London, England

8.Shandong Acad Agr Sci, Inst Agrofood Sci & Technol, Jinan, Shandong, Peoples R China

9.Xiamen Univ, Dept Phys, Innovat Ctr Cell Signaling Network, Xiamen, Peoples R China

10.Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Signaling Network, Xiamen, Peoples R China

11.China Agr Univ, Coll Vet Med, Beijing, Peoples R China

12.Chinese Peoples Liberat Army Gen Hosp, Dept Gastroenterol & Hepatol, Beijing, Peoples R China

13.Huazhong Univ Technol & Sci, Div Gastroenterol, Union Hosp, Tongji Med Coll, Wuhan, Hubei, Peoples R China

14.Fourth Mil Med Univ, Dept Gastroenterol, Xijing Hosp, Xian, Shaanxi, Peoples R China

15.Peking Univ, Med Res Ctr, Dept Radiat Oncol, Hosp 3, Beijing, Peoples R China

16.Dept Anat Histol & Embryol, Lab Mol Cell Biol & Tumor Biol, Beijing, Peoples R China

17.Univ Calif Irvine, Dept Dev & Cell Biol, Sue & Bill Gross Stem Cell Res Ctr, Ctr Complex Biol Syst, Irvine, CA USA

18.Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA

19.Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA

20.Univ Penn, Inst Regenerat Med, Philadelphia, PA 19104 USA

关键词： IBD; Nanoparticle Delivery System; Post-transcriptional Processing; Gene Regulation

期刊名称：GASTROENTEROLOGY （ 影响因子：22.682； 五年影响因子：23.936 ）

ISSN： 0016-5085

年卷期： 2019 年 156 卷 8 期

页码：

收录情况： SCI

摘要： BACKGROUND & AIMS: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. METHODS: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31-knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nano-particles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome-MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry. RESULTS: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-kappa B activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL) 6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3' untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome-MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation. CONCLUSIONS: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome-MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556