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MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors

文献类型：期刊论文

作者Liu, Ronghua3,7; Lu, Zhou3,7; Liu, Jiajing3,7; Huang, Enyu3,7; Wang, Luman3,7; Wang, Zhiming3,7; Zhang, Hushan3,7; Jiang, Xuechao3,7; Zhang, Dan3,7; Qian, Jing3,7
刊名GASTROENTEROLOGY
出版日期2018
卷号154期号:3页码:637-+
关键词Immune Regulation Tumor Immunosuppression microRNA15A/16-1 Colon Cancer Model
ISSN号0016-5085
DOI10.1053/j.gastro.2017.09.045
文献子类Article
英文摘要BACKGROUND & AIMS: B cells infiltrate tumors, but little is known about how they affect tumor growth and progression. microRNA15A (MIR15A or miRNA15A) and microRNA16-1 (MIR16-1 or miRNA16-1) regulate cell proliferation, apoptosis, and drug resistance. We investigated their involvement in B-cell-mediated immune suppression by colorectal tumors. METHODS: Mice with disruptions of the gene cluster that encodes MIR15A and MIR16-1 (knockout mice), and control (C57BL/B6) mice were given azoxymethane with dextran sodium sulfate (AD) to induce formation of colorectal tumors. Mice were given anti-CD20 to delete B cells, or injections of agomir to increase MIR15A and MIR16-1. Proliferation of CD8(+)T cells was measured by carboxyfluorescein-succinimidyl-ester analysis. Colon tissues were collected from mice and analyzed by flow cytometry, microRNA (miRNA) sequencing, and for cytokine production. Intestinal epithelial cells (IECs) were isolated and transfected with miRNA mimics, to identify their targets. We analyzed miRNA expression patterns and quantified B cells in colorectal cancer tissue microarrays derived from 90 patients who underwent surgical resection, from July 2006 through April 2008, in Shanghai, China; expression data were compared with clinical outcomes. RESULTS: Tumors that developed in knockout mice following administration of AD were larger and contained greater numbers of B cells than tumors that grew in control mice. Most of the B cells in the tumors were positive for immunoglobulin A (IgA(+)). IgA(+) B cells expressed high levels of immune regulatory molecules (programmed death ligand 1, interleukin 10, and transforming growth factor beta), and repressed the proliferation and activation of CD8(+) T cells. Levels of MIR15A and MIR16-1 were reduced in colon tumors from mice, compared with nontumor colon tissue. Incubation of IECs with IL17A reduced expression of MIR15A and MIR16-1. Transgenic expression of MIR15A and MIR16-1 in IECs decreased activation of NF-kappa B and STAT1 by reducing expression of I-kappaB kinases; this resulted in reduced production of chemokine (C-X-C motif) ligands 9 and 10 and decreased chemotaxis of IgA(+) B cells. Tumors in mice injected with AD and agomir grew more slowly than tumors in mice not given in agomir and contained fewer IgA(+) B cells. We found a negative correlation between levels of MIR15A and MIR16-1 and numbers of IgA(+)B cells in human colorectal tumor tissues; high levels of MIR15A and MIR16-1 and low numbers of IgA(+)B cells were associated with longer survival times of patients. CONCLUSIONS: We found increased levels of MIR15A and MIR16-1 to reduce numbers of IgA(+)B cells in colorectal tumor tissues and correlate with increased survival time of patients. In mice that lack MIR15A and MIR16-1, colon tumors grow more rapidly and contain increased numbers of IgA(+)B cells. MIR15A and MIR16-1 appear to activate signaling pathways required for B-cell-mediated immune suppression.
学科主题Gastroenterology & Hepatology
WOS关键词COLITIS-ASSOCIATED CANCER ; INFLAMMATORY RESPONSE ; PD-1 BLOCKADE ; PLASMA-CELLS ; INFECTION ; IGA ; TUMORIGENESIS ; MALIGNANCIES ; EXPRESSION ; CARCINOMA
语种英语
WOS记录号WOS:000424741500035
出版者W B SAUNDERS CO-ELSEVIER INC
版本出版稿
源URL[http://202.127.25.144/handle/331004/502]  
专题中国科学院上海生命科学研究院营养科学研究所
作者单位1.Peking Univ, Shenzhen Hosp, Dept Dermatol, Shenzhen, Guangdong, Peoples R China;
2.Fudan Univ, Biotherapy Res Ctr, Shanghai, Peoples R China;
3.Fudan Univ, Sch Basic Med Sci, Dept Immunol, 138 Yi Xue Yuan Rd,Mail Box 226, Shanghai 200032, Peoples R China;
4.Fudan Univ, Huashan Hosp, Div Surg Pathol, Shanghai, Peoples R China;
5.Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai, Peoples R China;
6.Tongji Univ, Shanghai Peoples Hosp 10, Dept Gastroenterol, Shanghai, Peoples R China,
7.Fudan Univ, Sch Basic Med Sci, Inst Biomed Sci, 138 Yi Xue Yuan Rd,Mail Box 226, Shanghai 200032, Peoples R China;
8.Fudan Univ, Dept Thorac Surg, Affiliated Zhongshan Hosp, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Liu, Ronghua,Lu, Zhou,Liu, Jiajing,et al. MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors[J]. GASTROENTEROLOGY,2018,154(3):637-+.
APA Liu, Ronghua.,Lu, Zhou.,Liu, Jiajing.,Huang, Enyu.,Wang, Luman.,...&,.(2018).MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors.GASTROENTEROLOGY,154(3),637-+.
MLA Liu, Ronghua,et al."MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors".GASTROENTEROLOGY 154.3(2018):637-+.

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来源：上海营养与健康研究所

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