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首页> 外文期刊>Gastroenterology >Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor-kappa B, and Up-regulating Expression of MicroRNA-21
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Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor-kappa B, and Up-regulating Expression of MicroRNA-21

机译：Fusobacterium核心通过激活Toll样受体4信号传导至核因子-Kappa B，增加小鼠的结肠直肠癌细胞和肿瘤发育的增殖，以及MicroRNA-21的上调表达

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摘要

BACKGROUND & AIMS: Nearly 20% of the global cancer burden can be linked to infectious agents. Fusobacterium nucleatum promotes tumor formation by epithelial cells via unclear mechanisms. We aimed to identify microRNAs (miRNAs) induced by F nucleatum and evaluate their ability to promote colorectal carcinogenesis in mice. METHODS: Colorectal cancer (CRC) cell lines were incubated with F nucleatum or control reagents and analyzed in proliferation and would healing assays. HCT116, HT29, LoVo, and SW480 CRC cell lines were incubated with F nucleatum or phosphate-buffered saline (PBS [control]) and analyzed for miRNA expression patterns and in chromatin immunoprecipitation assays. Cells were incubated with miRNAs mimics, control sequences, or small interfering RNAs; expression of reporter constructs was measured in luciferase assays. CRC cells were incubated with F nucleatum or PBS and injected into BALB/C nude mice; growth of xenograft tumors was measured. C57BL adenomatous polyposis coli(min/+), C57BL miR21a(-/-), and C57BL mice with full-length miR21a (controls) were given F nucleatum by gavage; some mice were given azoxymethane and dextran sodium sulfate to induce colitis and colon tumors. Intestinal tissues were collected and tumors were counted. Serum samples from mice were analyzed for cytokine levels by enzyme-linked immunosorbent assay. We performed in situ hybridization analyses to detect enrichment of F nucleatum in CRC cells. Fusobacterium nucleatum DNA in 90 tumor and matched nontumor tissues from patients in China were explored for the expression correlation analysis; levels in 125 tumor tissues from patients in Japan were compared with their survival times. RESULTS: Fusobacterium nucleatum increased proliferation and invasive activities of CRC cell lines compared with control cells. CRC cell lines infected with F nucleatum formed larger tumors, more rapidly, in nude mice than uninfected cells. Adenomatous polyposis coli(min/+) mice gavaged with F nucleatum developed significantly more colorectal tumors than mice given PBS and had shorter survival times. We found several inflammatory factors to be significantly increased in serum from mice given F nucleatum (interleukin 17F, interleukin 21, and interleukin 22, and MIP3A). We found 50 miRNAs to be significantly up-regulated and 52 miRNAs to be significantly down-regulated in CRCs incubated with F nucleatum vs PBS; levels of miR21 increased by the greatest amount (>4-fold). Inhibitors of miR21 prevented F nucleatum from inducing cell proliferation and invasion in culture. miR21a(-/-) mice had a later appearance of fecal blood and diarrhea after administration of azoxymethane and dextran sodium sulfate, and had longer survival times compared with control mice. The colorectum of miR21a(-/-) mice had fewer tumors, of smaller size, and the miR21a(-/-) mice survived longer than control mice. We found RASA1, which encodes an RAS GTPase, to be one of the target genes consistently down-regulated in cells that overexpressed miR21 and up-regulated in cells exposed to miR21 inhibitors. Infection of cells with F nucleatum increased expression of miR21 by activating Toll-like receptor 4 signaling to MYD88, leading to activation of the nuclear factor-kappa B. Levels of F nucleatum DNA and miR21 were increased in tumor tissues (and even more so in advanced tumor tissues) compared with non-tumor colon tissues from patients.
机译：背景和目标：近20％的全球癌症负担可以与传染病有关。 Fusobacterium核核心通过不明确的机制促进上皮细胞的肿瘤形成。我们的旨在鉴定由核遗迹诱导的MicroRNAS（miRNA），并评估它们在小鼠中促进结肠直肠癌的能力。方法：与F核细胞或对照试剂一起孵育结直肠癌（CRC）细胞系，并在增殖中进行分析，并愈合测定。 HCT116，HT29，LOVO和SW480 CRC细胞系与F核形毒或磷酸盐缓冲盐水（PBS [控制]）孵育，并分析MiRNA表达模式和染色质免疫沉淀测定。将细胞与miRNA模拟，对照序列或小干扰RNA一起温育;在荧光素酶测定中测量报告构建体的表达。将CRC细胞与F核细胞或PBS一起温育，并注入Balb / C裸鼠;测量异种移植肿瘤的生长。通过饲养给出C 57BL腺瘤性息肉（Min / +），C57BL miR21a（ - / - ）和具有全长MiR21a（对照）的C57BL小鼠;将一些小鼠给予氮氧基甲烷和葡聚糖硫酸钠以诱导结肠炎和结肠肿瘤。收集肠组织，计算肿瘤。通过酶联免疫吸附测定分析来自小鼠的血清样品进行细胞因子水平。我们在原位杂交分析中进行以检测CRC细胞中F成核的富集。探讨了90例肿瘤和来自中国患者的与匹配的Nontumor组织中的核核DNA进行了表达相关性分析;将日本患者的125例肿瘤组织中的水平与其存活时间进行比较。结果：与对照细胞相比，Fusobacterium成核核癌增加和侵入性CRC细胞系的侵袭性。 CRC细胞系感染F核来形成较大的肿瘤，更快地在裸鼠中比未感染的细胞更快。用F成核来妊娠的腺瘤性息肉（Min / +）小鼠比给予PBS的小鼠显着显着显着结直肠癌，并且存活时间较短。在给定F核（白细胞介素17F，白细胞介素21和白细胞介素22和MIP3A）中，我们发现几种炎症因子在来自小鼠的血清中显着增加。我们发现50 miRNA是明显上调的，52名miRNA在与F核VS PBS孵育的CRCS中显着下调; MIR21的水平增加了最大的量（> 4倍）。 miR21的抑制剂阻止了核癌诱导培养细胞增殖和侵袭。 MiR21a（ - / - ）小鼠在施用亚唑缩甲烷和葡聚糖硫酸钠后患有粪便血液和腹泻的后面外观，并与对照小鼠进行更长的存活时间。 miR21a（ - / - ）小鼠的结肠凝乳具有较少的肿瘤，尺寸的尺寸较少，并且mir21a（ - / - ）小鼠比对照小鼠更长。我们发现将RasA1编码为RAS GTP酶，是在暴露于miR21抑制剂暴露于miR21抑制剂的细胞中的细胞中始终如一地下调的靶基因之一。用F成核来感染细胞通过激活Toll样受体4信号传导至MyD88的MiR21的表达增加，导致核因子-Kappa B.肿瘤组织中的核因子-Kappa B.和MiR21的水平增加（甚至更为含量高级肿瘤组织）与来自患者的非肿瘤结肠组织相比。

著录项

  • 来源
    《Gastroenterology》 |2017年第4期|共40页
  • 作者

    Yang Yongzhi; Weng Wenhao; Peng Junjie; Hong Leiming; Yang Lei; Toiyama Yuji; Gao Renyuan; Liu Minfeng; Yin Mingming; Pan Cheng; Li Hao; Guo Bomin; Zhu Qingchao; Wei Qing; Moyer Mary-Pat; Wang Ping; Cai Sanjun; Goel Ajay; Qin Huanlong; Ma Yanlei;

  • 作者单位

    Fudan Univ Dept Colorectal Surg Shanghai Canc Ctr 270 Dongan Rd Shanghai 200032 Peoples R China;

    Baylor Scott &

    White Res Inst Ctr Translat Genom &

    Oncol Ctr Gastrointestinal Res 3410 Worth St;

    Fudan Univ Dept Colorectal Surg Shanghai Canc Ctr 270 Dongan Rd Shanghai 200032 Peoples R China;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Mie Univ Grad Sch Med Dept Gastrointestinal &

    Pediat Surg Div Reparat Med Inst Life Sci Tsu;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Shanghai Jiao Tong Univ Dept Surg Affiliated Peoples Hosp 6 Shanghai Peoples R China;

    Shanghai Jiao Tong Univ Dept Surg Affiliated Peoples Hosp 6 Shanghai Peoples R China;

    Tongji Univ Dept Pathol Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    INCELL Corp San Antonio TX USA;

    Tongji Univ Shanghai Peoples Hosp 10 Sch Life Sci &

    Technol Dept Cent Lab Shanghai Peoples R;

    Fudan Univ Dept Colorectal Surg Shanghai Canc Ctr 270 Dongan Rd Shanghai 200032 Peoples R China;

    Baylor Scott &

    White Res Inst Ctr Translat Genom &

    Oncol Ctr Gastrointestinal Res 3410 Worth St;

    Tongji Univ Dept Gastrointestinal Surg Shanghai Peoples Hosp 10 Shanghai Peoples R China;

    Fudan Univ Dept Colorectal Surg Shanghai Canc Ctr 270 Dongan Rd Shanghai 200032 Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 消化系及腹部疾病;
  • 关键词

    Microbe; Signal Transduction; Gene Regulation; Carcinogenesis;

    机译：微生物;信号转导;基因调节;致癌物;

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