MTA1 aggravates experimental colitis in mice by promoting transcription factor HIF1A and up-regulating AQP4 expression.
MTA1 aggravates experimental colitis in mice by promoting transcription factor HIF1A and up-regulating AQP4 expression.
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DOI：
10.1038/s41420-022-01052-y
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发表时间：
2022-06-28
影响因子：
7
通讯作者：
Wang, Liu-Hua
中科院分区：
文献类型：
--
作者：
Li, Ping;Shi, Dong-Ping;Jin, Tao;Tang, Dong;Wang, Wei;Wang, Liu-Hua
实验性结肠炎可以作为一种慢性疾病持续存在，伴随着发展成结直肠癌的潜在风险。转移相关蛋白1（MTA 1）作为一种染色质修饰剂，与包括结肠炎在内的多种疾病有着显著的相关性。本研究旨在探讨MTA 1/HIF 1A/AQP 4轴在小鼠实验性结肠炎中的作用机制。首先，建立葡聚糖硫酸钠（DSS）诱导的小鼠实验性结肠炎模型，并采用脂多糖（LPS）诱导的体外结肠上皮细胞FHC炎症模型，检测MTA 1和HIF 1A的表达。结果发现，MTA 1和HIF 1A在实验性结肠炎样品中均高表达。双荧光素酶报告基因检测和ChIP检测结果进一步显示，MTA 1激活HIF 1A，随后诱导AQP 4转录，上调AQP 4表达。采用TUNEL染色结合流式细胞术和CCK-8法检测MTA 1/HIF 1A/AQP 4轴对结肠上皮细胞凋亡和存活的影响。在FHC和NCM 460细胞中观察到MAT 1的沉默降低了LPS诱导的IL-1β和TNF-α的表达。同时，AQP 4可促进LPS诱导的炎症反应，加剧结肠上皮细胞凋亡，促进小鼠实验性结肠炎的发生发展。体内实验进一步证实，TGN-020治疗有效减轻DSS诱导的小鼠实验性结肠炎，并减少结肠上皮细胞的凋亡。总而言之，MTA 1可能通过激活HIF 1A促进AQP 4转录，从而加剧DSS诱导的小鼠实验性结肠炎，这为实验性结肠炎的治疗提供了新的方向。
Experimental colitis can persist as a chronic disease, accompanied with an underlying risk of development into colorectal cancer. Metastasis-associated protein 1 (MTA1), as a chromatin modifier, exerts notable association with multiple diseases, including colitis. The current study aims to investigate the mechanism of MTA1/HIF1A/AQP4 axis in experimental colitis in mice. First, experimental colitis mouse models were established using dextran sulfate sodium (DSS) and in vitro colonic epithelial cells FHC inflammation models were with lipopolysaccharide (LPS) for determination of MTA1 and HIF1A expressions. It was found that MTA1 and HIF1A were both highly-expressed in experimental colitis samples. Results of dual-luciferase reporter gene assay and ChIP assay further revealed that MTA1 activated HIF1A, and subsequently induced AQP4 transcription to up-regulate AQP4 in experimental colitis. Following loss- and gain-function, the effects of MTA1/HIF1A/AQP4 axis on apoptosis and viability of colon epithelial cells were detected by a combination of TUNEL staining and flow cytometry, and CCK-8 assay. It was observed that silencing of MAT1 in the FHC and NCM460 cells reduced IL-1β and TNF-α expressions induced by LPS. Meanwhile, AQP4 promoted LPS-induced inflammation, and exacerbated apoptosis of colon epithelial cells and augmented experimental colitis development in mice. In vivo experiments further verified that TGN-020 treatment effectively alleviated DSS-induced experimental colitis in mice and diminished apoptosis of colon epithelial cells. Altogether, MTA1 may promote AQP4 transcription by activating HIF1A, thus exacerbating DSS-induced experimental colitis in mice, which provides a novel direction for the treatment of experimental colitis.
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影响因子：
5.2
作者：
Garcia-Hernandez V;Quiros M;Nusrat A
通讯作者：
Nusrat A
DOI：
10.1016/j.bbrc.2019.09.078
发表时间：
2019-11-26
影响因子：
3.1
作者：
Guddeti, Rohith Kumar;Bali, Prerna;Pakala, Suresh B.
通讯作者：
Pakala, Suresh B.
影响因子：
4.8
作者：
Hubbi, Maimon E.;Hu, Hongxia;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
6.3
作者：
Umschweif, Gali;Alexandrovich, Alexander G.;Shohami, Esther
通讯作者：
Shohami, Esther
水通道蛋白 4 缺乏可减轻小鼠实验性结肠炎
影响因子：
4.8
作者：
Wang, Liuhua;Tang, Hua;Shen, Lizong
通讯作者：
Shen, Lizong