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. (31st March 2022)

• Record Type: Journal Article
• Authors: Tang, Kaiwen; Wu, Zhonghua; Sun, Mingwei; Huang, Xuanzhang; Sun, Jingxu; Shi, Jinxin; Wang, Xin; Miao, Zhifeng; Gao, Peng; Song, Yongxi; Wang, Zhenning
• Is Part Of: Cancer letters. Volume 529(2022)
• Page Start: 53
• Page End: 69
• Publication Date: 2022-03-31
• Subjects: miRNAs -- Colitis -- Colitis-associated colon cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.12.033
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: We firstly constructed knockout (KO) mice for individual miR-148/152 family members and the entire miR-148/152 family. Deleting miR-148/152 family members caused overexpression of targeted genes MMP10, MMP13, IKKα and IKKβ. MiR-148/152 family deficiency upregulated MMP10/13, resulting in TNF-α maturation and sequential NF-κB pathway activation. MiR-148/152 family deficiency mediated IKKα/β overexpression could activate NF-κB signaling pathway. Our findings suggest impeding NF-κB pathway could treat colitis or colon cancer patients with miR-148/152 downregulation.