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Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-06-01 , DOI: 10.1016/j.jcmgh.2020.05.010
Yong-Guo Zhang 1 , Rong Lu 1 , Shaoping Wu 2 , Ishita Chatterjee 1 , David Zhou 3 , Yinglin Xia 1 , Jun Sun 4
Affiliation  

Background & Aims

Vitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in tumorigenesis.

Methods

To test our hypothesis, we used an azoxymethane/dextran sulfate sodium–induced cancer model in intestinal VDR conditional knockout (VDRΔIEC) mice, cell cultures, stem cell–derived colonoids, and human colon cancer samples.

Results

VDRΔIEC mice have higher numbers of tumors, with the location shifted from the distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to a bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDRΔIEC mice showed increased secondary bile acids, consistent with observations in human CRC. We further identified that VDR protein bound to the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/STAT pathway is critical in intestinal and microbial homeostasis. Fecal samples from VDRΔIEC mice activate the STAT3 signaling in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in response to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3.

Conclusions

We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target: microbiome and VDR for the prevention of cancer.



中文翻译:

维生素 D 受体通过肠道中的 JAK/STAT 通路防止生态失调和肿瘤发生。

背景与目标

维生素 D 通过维生素 D 受体 (VDR) 在粘膜免疫、宿主防御以及涉及宿主因素和微生物组的炎症中发挥调节作用。人类Vdr基因变异塑造微生物组,VDR 缺失导致生态失调。在结肠癌中观察到低 VDR 表达和维生素 D/VDR 信号减弱。然而,肠上皮 VDR 如何通过肠道微生物群参与肿瘤发生仍然未知。我们假设肠道 VDR 通过调节肿瘤发生中的 Janus 激酶 (JAK)/信号转导和转录激活因子 (STAT) 通路来保护小鼠免受生态失调。

方法

为了验证我们的假设,我们在肠道 VDR 条件敲除 (VDR ΔIEC ) 小鼠、细胞培养物、干细胞衍生的结肠样体和人类结肠癌样本中使用了氧化偶氮甲烷/硫酸葡聚糖钠诱导的癌症模型。

结果

VDR ΔIEC小鼠的肿瘤数量较多,位置从远端结肠转移到近端结肠。粪便微生物群分析表明,VDR 缺失导致细菌谱从正常致癌转变为易感致癌作用。我们发现小鼠和人类肿瘤中的细菌染色增强。来自 VDR ΔIEC小鼠的微生物代谢物显示出次级胆汁酸增加,这与人类 CRC 中的观察结果一致。我们进一步确定 VDR 蛋白与 Jak2 启动子结合,表明 VDR 转录调节 Jak2。JAK/STAT 通路对肠道和微生物稳态至关重要。来自 VDR ΔIEC 的粪便样本小鼠激活人和小鼠类器官中的 STAT3 信号。VDR 的缺乏导致 Jak2 功能亢进以应对肠道菌群失调。JAK/STAT 抑制剂消除了微生物组诱导的 STAT3 激活。

结论

我们深入了解 VDR 功能障碍导致生态失调和肿瘤发生的机制。它表明了一个新的目标:微生物组和 VDR 用于预防癌症。

更新日期:2020-06-01
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