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Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1.

ABSTRACT: Emerging evidence indicates that microRNAs (miRNAs) play fundamental roles in the pathogenesis of multiple diseases, including acute lung injury (ALI). Here, we discovered that miR-199a-3p was significantly downregulated in ALI lung tissues using a microarray analysis. In vitro lipopolysaccharide (LPS) treatment of the human epithelial cell line A549 and the human macrophage cell line U937 caused a decrease of miR-199a-3p. Mechanically, miR-199a-3p specifically bound to the 3'-untranslated region (3'-UTR) of NLRP1 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 1), a critical member of inflammasomes. Ectopic overexpression or downregulation of miR-199a-3p resulted in the repression or induction of NLRP1, respectively, thereby downregulating or activating its downstream events. Moreover, transcription factor FOXP3 (forkhead box P3) was able to specifically bind to the promoter of miR-199a-3p. Knockdown or overexpression of FOXP3 resulted in a decrease or induction miR-199a-3p expression, respectively. Using immunoprecipitation (IP), mass spectrometry and co-IP assays, we found that FOXP3 formed a transcriptional complex with HDAC1 (histone deacetylase 1) and CtBP2 (C-terminal-binding protein 2). Collectively, our results suggested that the CtBP2-HDAC1-FOXP3 transcriptional complex (CHFTC) could specifically bind to the promoter of miR-199a-3p and repress its expression. Downregulation of miR-199a-3p eliminated its inhibition of NLRP1, causing activation of NLRP1 and cleavage of pro-IL-1? and pro-IL-18 mediated by Caspase-1. The secretion of IL-1? and IL-18 further aggravated the inflammatory response and resulted in the occurrence of ALI.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6854378 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting <i>NLRP1</i>.

Chen Zhi Z Dong Wei-Hua WH Chen Qiang Q Li Qiu-Gen QG Qiu Zhong-Min ZM

International journal of biological sciences 20190908 12

Emerging evidence indicates that microRNAs (miRNAs) play fundamental roles in the pathogenesis of multiple diseases, including acute lung injury (ALI). Here, we discovered that miR-199a-3p was significantly downregulated in ALI lung tissues using a microarray analysis. <i>In vitro</i> lipopolysaccharide (LPS) treatment of the human epithelial cell line A549 and the human macrophage cell line U937 caused a decrease of miR-199a-3p. Mechanically, miR-199a-3p specifically bound to the 3'-untranslate ...[more]

PMID: 31754335

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Project description:BackgroundIt was previously demonstrated that miR-199a-3p plays an important role in tumor progression; especially, its down-regulation in papillary thyroid cancer (PTC) is associated with cancer cell invasion and proliferation. In the present report, we investigated the mechanism involved in the down-regulation of miR-199a-3p in PTC and how miR-199a-3p regulates PTC invasion both in vivo and in vitro.MethodsqRT-PCR and Western blot assays were used to determine the expression of the investigated genes. Bisulfite sequencing PCR was used to investigate miR-199a-3p methylation. The functions of miR-199a-3p were investigated by a series of in vitro and in vivo experiments.ResultsOur results showed hypermethylation of the miR-199a-3p promoter, which resulted in decreased miR-199a-3p expression both in PTC cell lines and PTC tissues. DNA-methyltransferase 3a (DNMT3a), a target gene of miR-199a-3p, was increased both in PTC cell lines and PTC tissues, while 5-aza-2'-deoxycytidine (methyltransferase-specific inhibitor) or knock-down using DNMT3a Small-Interfering RNA could restore the expression of miR-199a-3p, and the over-expression of miR-199a-3p could decrease the expression of DNMT3a; this suggests that miR-199a-3p/DNMT3a constructs a regulatory circuit in regulating miR-199a-3p/DNMT3a expression. Moreover, gain- and loss-of-function studies revealed that miR-199a-3p is involved in cancer cell migration, invasion, and growth. Meanwhile, we found that RAP2a was also a direct target of miR-199a-3p, which might mediate the tumor-growth-inhibiting effect of miR-199a-3p. To further confirm the tumor-suppressive properties of miR-199a-3p, stable overexpression of miR-199a-3p in a PTC cell line (BCPAP cells) was xenografted to athymic BALB/c nude mice, resulting in delayed tumor growth in vivo. In clinical PTC samples, the expression of RAP2a and DNMT3a was increased significantly, and the expression of RAP2a was inversely correlated with that of miR-199a-3p.ConclusionOur studies demonstrate that an epigenetic change in the promoter region of miR-199a contributes to the aggressive behavior of PTC via the miR-199a-3p/DNMT3a regulatory circuit and directly targets RAP2a.

Dataset Information

Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1.

Publications

Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting <i>NLRP1</i>.

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