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MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors.
Gastroenterology. 2018 02; 154(3):637-651.e7.G

Abstract

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-κB 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.

Authors+Show Affiliations

Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Thoracic Surgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Dermatology, Shenzhen Hospital, Peking University, Shenzhen, Guangdong, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Biotherapy Research Center, Fudan University, Shanghai, P.R. China.Biotherapy Research Center, Fudan University, Shanghai, P.R. China.Biotherapy Research Center, Fudan University, Shanghai, P.R. China.Biotherapy Research Center, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China.Division of Surgical Pathology, Huashan Hospital, Fudan University, Shanghai, P.R. China.Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai, P.R. China.Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, P.R. China.Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China; Biotherapy Research Center, Fudan University, Shanghai, P.R. China. Electronic address: yiwei_chu@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29031499

Citation

Liu, Ronghua, et al. "MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B Cells to Colorectal Tumors." Gastroenterology, vol. 154, no. 3, 2018, pp. 637-651.e7.
Liu R, Lu Z, Gu J, et al. MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors. Gastroenterology. 2018;154(3):637-651.e7.
Liu, R., Lu, Z., Gu, J., Liu, J., Huang, E., Liu, X., Wang, L., Yang, J., Deng, Y., Qian, J., Luo, F., Wang, Z., Zhang, H., Jiang, X., Zhang, D., Qian, J., Liu, G., Zhu, H., Qian, Y., ... Chu, Y. (2018). MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors. Gastroenterology, 154(3), 637-e7. https://doi.org/10.1053/j.gastro.2017.09.045
Liu R, et al. MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B Cells to Colorectal Tumors. Gastroenterology. 2018;154(3):637-651.e7. PubMed PMID: 29031499.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors. AU - Liu,Ronghua, AU - Lu,Zhou, AU - Gu,Jie, AU - Liu,Jiajing, AU - Huang,Enyu, AU - Liu,Xiaoming, AU - Wang,Luman, AU - Yang,Jiao, AU - Deng,Yuting, AU - Qian,Jiawen, AU - Luo,Feifei, AU - Wang,Zhiming, AU - Zhang,Hushan, AU - Jiang,Xuechao, AU - Zhang,Dan, AU - Qian,Jing, AU - Liu,Guangwei, AU - Zhu,Hongguang, AU - Qian,Youcun, AU - Liu,Zhanju, AU - Chu,Yiwei, Y1 - 2017/10/12/ PY - 2017/03/25/received PY - 2017/09/11/revised PY - 2017/09/30/accepted PY - 2017/10/17/pubmed PY - 2018/5/4/medline PY - 2017/10/17/entrez KW - Colon Cancer Model KW - Immune Regulation KW - Tumor Immunosuppression KW - microRNA15A/16–1 SP - 637 EP - 651.e7 JF - Gastroenterology JO - Gastroenterology VL - 154 IS - 3 N2 - 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-κB 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/29031499/MicroRNAs_15A_and_16_1_Activate_Signaling_Pathways_That_Mediate_Chemotaxis_of_Immune_Regulatory_B_cells_to_Colorectal_Tumors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(17)36240-6 DB - PRIME DP - Unbound Medicine ER -