Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice.
Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice.
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DOI：
10.1016/j.canlet.2021.12.033
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发表时间：
2021-12
期刊：
影响因子：
9.7
通讯作者：
Kaiwen Tang;Zhonghua Wu;Mingwei Sun;Xuan-Zhang Huang;Jingxu Sun;Jinxin Shi;Xin Wang;Z. Miao;P. Gao;Yongxi Song;Zhen-ning Wang
中科院分区：
文献类型：
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作者：
Kaiwen Tang;Zhonghua Wu;Mingwei Sun;Xuan-Zhang Huang;Jingxu Sun;Jinxin Shi;Xin Wang;Z. Miao;P. Gao;Yongxi Song;Zhen-ning Wang
已知动态miRNA改变发生在结肠炎相关性结肠癌（CAC）中，而支持miRNA如何调节从慢性炎症到CAC的发展的分子机制缺乏。我们首次构建了miR-148/152家族成员和整个miR-148/152家族的敲除小鼠。基于这些KO小鼠，我们首次对miR-148/152家族进行了全面分析，证明miR-148/152家族任何成员的缺乏都会加重结肠炎和CAC。单个miR-148/152家族成员或全家族的缺失可增强MMP 10和MMP 13的表达，导致肠屏障破坏，并将pro-TNF-α裂解为生物活性TNF-α片段，从而激活NF-κB信号传导，从而加重结肠炎。单个和全家族缺失也会增加IKKα和IKKβ的蓄积，导致NF-κB信号进一步过度激活，加重结肠炎和CAC。此外，阻断NF-κB信号传导仅在KO小鼠中对结肠炎和CAC模型发挥恢复作用。总之，这些发现表明删除完整的miR-148/152家族或单个成员在结肠炎和CAC中表现出相似的作用。在机制上，小鼠中的miR-148/152家族成员缺陷通过破坏肠屏障功能和激活NF-κB信号传导来升高MMP 10和MMP 13以加速结肠炎和CAC，这表明结肠炎和CAC的潜在治疗策略。
Dynamic miRNA alteration is known to occur in colitis-associated colon cancer (CAC), while the molecular mechanisms underpinning how miRNAs modulate the development from chronic inflammation to CAC is lacking. For the first time, we constructed knockout (KO) mice for individual miR-148/152 family members and entire miR-148/152 family. Based on these KO mice, we conduct the first comprehensive analysis of miR-148/152 family, demonstrating that deficiency of any member of miR-148/152 family aggravate colitis and CAC. Loss of individual miR-148/152 family members or full-family enhance MMP10 and MMP13 expression, causing disruption of intestinal barrier and cleaving pro-TNF-α into bioactive TNF-α fragments to activate NF-κB signaling, thereby aggravating colitis. Individual and full-family deletion also increase accumulation of IKKα and IKKβ, resulting in further hyperactivation of NF-κB signaling, exacerbating colitis and CAC. Moreover, blocking NF-κB signaling exerts a restorative effect on colitis and CAC models only in KO mice. Taken together, these findings demonstrate deleting the full miR-148/152 family or individual members exhibit similar effects in colitis and CAC. Mechanically, miR-148/152 family members deficiency in mice elevates MMP10 and MMP13 to accelerate colitis and CAC via disrupting intestinal barrier function and activating NF-κB signaling, suggesting a potential therapeutic strategy for colitis and CAC.