Department of Microbiology, Second Military Medical University, Shanghai, 200433, China.
Cell Death Dis. 2019 Dec 20;10(12):958. doi: 10.1038/s41419-019-2186-9.
Inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Although some studies reported the roles of Retinoid acid induced 16 (RAI16) in the tumorigenesis of hepatocellular carcinoma and PKA signaling, the roles of RAI16 in IBD and CRC are undressed. RAI16 mice were generated and the roles of RAI16 were addressed in dextran sodium sulfate (DSS) or azoxymethane (AOM)-DSS induced IBD or CAC mouse models, respectively. At first, RAI16 mice were viable, fertile with no apparent defects. Then, it was found that RAI16 mice were more susceptibility to colitis induced by DSS than wild type (WT) littermates, which was evaluated by disease activity index and histological score. Furthermore, the expressions of tissues repair associated molecules Cox2, Ereg and MMP-10 were significantly decreased in RAI16 colon under DSS treatment. Gut barrier related genes including antimicrobial peptides Reg3b and Reg3g and intestinal mucus genes Muc4, Muc6 and Muc20 were reduced in RAI16 colon. These findings indicated that RAI16 may function to affect genes involved in intestinal barrier function and immunoprotective inflammation. Accordingly, RAI16 mice displayed significantly increased tumor burden compared with WT mice assessed in CAC model induced by AOM/DSS. Much more Ki67 + nuclei were observed in RAI16 tumors suggesting RAI16 to be critical in colonic cell proliferation during tumorigenesis. Conclusively, we demonstrate the roles of RAI16 in colonic inflammation and inflammation-associated tumorigenesis by using a novel RAI16 mouse model for the first time.
炎症性肠病（IBD）和结肠炎相关结直肠癌（CAC）是一个严重的健康问题，但发病的病理因素仍不清楚。虽然一些研究报道了维甲酸诱导蛋白 16（RAI16）在肝癌和 PKA 信号转导中的肿瘤发生作用，但 RAI16 在 IBD 和 CRC 中的作用尚未阐明。我们生成了 RAI16 小鼠，并分别在葡聚糖硫酸钠（DSS）或氧化偶氮甲烷（AOM）-DSS 诱导的 IBD 或 CAC 小鼠模型中研究了 RAI16 的作用。首先，RAI16 小鼠具有活力，可育，没有明显的缺陷。然后，我们发现 RAI16 小鼠对 DSS 诱导的结肠炎比野生型（WT）同窝仔鼠更易感，这可以通过疾病活动指数和组织学评分来评估。此外，在 DSS 处理下，RAI16 结肠中组织修复相关分子 Cox2、Ereg 和 MMP-10 的表达明显降低。肠道屏障相关基因，包括抗菌肽 Reg3b 和 Reg3g 以及肠粘液基因 Muc4、Muc6 和 Muc20 在 RAI16 结肠中减少。这些发现表明，RAI16 可能通过影响与肠道屏障功能和免疫保护炎症相关的基因来发挥作用。因此，与 WT 小鼠相比，在 AOM/DSS 诱导的 CAC 模型中，RAI16 小鼠的肿瘤负担明显增加。在 RAI16 肿瘤中观察到更多的 Ki67+核，这表明 RAI16 在肿瘤发生过程中对结肠细胞增殖至关重要。总之，我们首次使用新型 RAI16 小鼠模型证明了 RAI16 在结肠炎症和炎症相关肿瘤发生中的作用。
