Ikuta Togo, Kurosumi Masafumi, Yatsuoka Toshimasa, Nishimura Yoji
Department of Cancer Prevention, Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
Division of Pathology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
Exp Cell Res. 2016 May 1;343(2):126-134. doi: 10.1016/j.yexcr.2016.03.012. Epub 2016 Mar 10.
Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc(Min/+)mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression.
肠道微生物与肠道免疫系统之间的复杂相互作用维持着肠道内环境稳定。肠道免疫失调可能导致炎症性疾病和肿瘤发生。我们之前已经证明芳烃受体(AhR)在肠道癌变过程中具有肿瘤抑制作用。在本研究中,我们通过组织化学分析研究了AhR在小鼠和人类肠道中的分布。在正常肠道中,AhR主要定位于固有层和淋巴滤泡中含有免疫细胞的基质。另一方面,在人类结肠癌肿瘤组织以及Apc(Min/+)小鼠发生的肿瘤组织中,AhR表达升高。在基质细胞和肿瘤细胞中均发现了AhR免疫染色。虽然在大多数情况下AhR定位于肿瘤细胞的细胞质中,但在一些细胞中也观察到了细胞核中的AhR。使用小干扰RNA(siRNA)敲低AhR会导致结肠癌细胞系中细胞生长显著促进。此外,在培养基中添加AhR配体激活AhR可抑制细胞生长。我们的研究结果表明,AhR的肿瘤抑制作用以两种不同方式发挥:在正常组织中,AhR通过调节肠道免疫与肿瘤预防相关,而在肿瘤细胞中,它参与生长抑制。
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