Hasegawa Kana, Kuwata Keiko, Yoshitake Jun, Shimomura Sayako, Uchida Koji, Shibata Takahiro
Graduate School of Bioagricultural Sciences, Nagoya University, Japan.
Institute of Transformative Bio-Molecules (ITbM), Nagoya University, Japan.
FEBS J. 2021 Mar;288(6):1906-1917. doi: 10.1111/febs.15557. Epub 2020 Sep 15.
Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Although IBDs increase the risk of colitis-associated colon cancer, the underlying mechanisms are not fully understood. Extracellular vesicles (EVs) are lipid-bound sacs that transport proteins, RNA, and lipids between cells and are key mediators of cellular communication in both physiological and pathological settings. EVs have been implicated in many cancer hallmarks, including uncontrolled tumor growth and metastasis. In this study, we investigated the effects of colon-derived EVs on the proliferation of fibroblasts. We used comparative proteomics to characterize protein profiles of colorectal EVs isolated from healthy mice (Con-EVs) and those with dextran sulfate sodium-induced colitis (IBD-EVs). The results showed that 109 proteins were upregulated in IBD-EVs. Notably, expression of epidermal growth factor receptor (EGFR), which plays important roles in cell proliferation and development, was increased in IBD-EVs. We then examined the effect of EVs on murine NIH3T3 fibroblasts and found that IBD-EVs significantly promoted cell proliferation in EGFR- and ERK-dependent manner. Our findings suggest that inflamed colon-derived EVs promote tumor development thorough activation of fibroblasts.
炎症性肠病（IBDs），如克罗恩病和溃疡性结肠炎，是胃肠道的慢性炎症性疾病。尽管IBDs会增加结肠炎相关结肠癌的风险，但其潜在机制尚未完全明确。细胞外囊泡（EVs）是脂质包裹的囊泡，可在细胞间运输蛋白质、RNA和脂质，是生理和病理环境中细胞通讯的关键介质。EVs与许多癌症特征有关，包括不受控制的肿瘤生长和转移。在本研究中，我们调查了结肠来源的EVs对成纤维细胞增殖的影响。我们使用比较蛋白质组学来表征从健康小鼠（Con-EVs）和硫酸葡聚糖钠诱导的结肠炎小鼠（IBD-EVs）中分离出的结肠EVs的蛋白质谱。结果显示，IBD-EVs中有109种蛋白质上调。值得注意的是，在细胞增殖和发育中起重要作用的表皮生长因子受体（EGFR）在IBD-EVs中的表达增加。然后，我们检测了EVs对小鼠NIH3T3成纤维细胞的影响，发现IBD-EVs以EGFR和ERK依赖的方式显著促进细胞增殖。我们的研究结果表明，炎症结肠来源的EVs通过激活成纤维细胞促进肿瘤发展。
