Circular RNA circFBXW4 suppresses hepatic fibrosis via targeting the miR-18b-3p/FBXW7 axis

Chen, Xin; Li, Hai-Di; Bu, Fang-tian; Li, Xiaofeng; Chen, Yu; Zhu, Sai; Wang, Jianan; Chen, Siyu; Sun, Ying‐Yin; Pan, Xue‐Yin; Yin, Na-Na; Xu, Jiejie; Huang, Cheng; Li, Jun

doi:10.7150/thno.42423

Cited by 65 publications

(49 citation statements)

References 41 publications

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“…3,12 With the extensive studies of circRNAs, an increasing number of circRNAs have been found to act as miRNA sponges and play important roles in disease initiation and progression. [55][56][57][58] Considering the homolog of circRNAs with parental genes, it is possible that circRNAs can serve as competing endogenous RNAs (ceRNAs) to regulate their linear counterparts. A recent study reported that circ-Sirt1 binds to miR-132/212 that interferes with SIRT1 mRNA, and it facilitates the expression of host gene SIRT1 in vascular smooth muscle cells (VSMCs).…”

Section: Circrnas Regulate the Transcription Of Parental Genesmentioning

confidence: 99%

Circular RNA: an important player with multiple facets to regulate its parental gene expression

Shao

Pan

Xiong

2021

Molecular Therapy - Nucleic Acids

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Section: Circrnas Regulate the Transcription Of Parental Genesmentioning

confidence: 99%

Circular RNA: an important player with multiple facets to regulate its parental gene expression

Shao

Pan

Xiong

2021

Molecular Therapy - Nucleic Acids

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“…Activated HSCs could undergo proliferation, senescence, apoptosis and reversion of transdifferentiation 4 . Dysregulation and dysfunction of the underlying pathways and genes for phenotypic transition and fate-decision of HSCs are involved in liver fibrogenesis, which could be at least partly ascribed to their epigenetic alterations including DNA methylation, histone acetylation and methylation, microRNAs and long non-coding RNAs 5 , 6 .…”

Section: Introductionmentioning

confidence: 99%

Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

et al. 2021

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Rationale: As the central hallmark of liver fibrosis, transdifferentiation of hepatic stellate cells (HSCs), the predominant contributor to fibrogenic hepatic myofibroblast responsible for extracellular matrix (ECM) deposition, is characterized with transcriptional and epigenetic remodeling. We aimed to characterize the roles of H3K27 methyltransferase EZH2 and demethylase JMJD3 and identify their effective pathways and novel target genes in HSCs activation and liver fibrosis. Methods: In primary HSCs, we analyzed effects of pharmacological inhibitions and genetic manipulations of EZH2 and JMJD3 on HSCs activation. In HSCs cell lines, we evaluated effects of EZH2 inhibition by DZNep on proliferation, cell cycling, senescence and apoptosis. In CCl 4 and BDL murine models of liver fibrosis, we assessed in vivo effects of DZNep administration and Ezh2 silencing. We profiled rat primary HSCs transcriptomes with RNA-seq, screened the pathways and genes associated with DZNep treatment, analyzed EZH2 and JMJD3 regulation towards target genes by ChIP-qPCR. Results: EZH2 inhibition by DZNep resulted in retarded growth, lowered cell viability, cell cycle arrest in S and G2 phases, strengthened senescence, and enhanced apoptosis of HSCs, decreased hepatic collagen deposition and rescued the elevated serum ALT and AST activities of diseased mice, and downregulated cellular and hepatic expressions of H3K27me3, EZH2, α-SMA and COL1A. Ezh2 silencing by RNA interference in vitro and in vivo showed similar effects. JMJD3 inhibition by GSK-J4 and overexpression of wild-type but not mutant Jmjd3 enhanced or repressed HSCs activation respectively. EZH2 inhibition by DZNep transcriptionally inactivated TGF-β1 pathway, cell cycle pathways and vast ECM components in primary HSCs. EZH2 inhibition decreased H3K27me3 recruitment at target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, and increased their expressions, while Jmjd3 overexpression manifested alike effects. Conclusions: EZH2 and JMJD3 antagonistically modulate HSCs activation. The therapeutic effects of DZNep as epigenetic drug in liver fibrosis are associated with the regulation of EZH2 towards direct target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, which are also regulated by JMJD3. Our present study provides new mechanistic insight into the epigenetic modulation of EZH2 and JMJD3 in HSCs biology and hepatic fibrogenesis.

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“…In our present study, we found that circPSD3 was expressed at abnormally low levels in primary HSCs of mice with CCl 4 -induced HF, consistent with our previous results. 21 Overexpression of circPSD3 via an AAV8-mediated gene delivery system in mice significantly alleviated CCl 4 -induced liver damage, cytokine-mediated inflammation, collagen deposition, and a-SMApositive region. Given the role of activated HSCs in hepatic fibrogenesis, we suspected that circPSD3 might play a crucial role in activation and proliferation of HSCs, thereby regulating hepatic fibrogenesis.…”

Section: Discussionmentioning

confidence: 95%

“…As previously shown, a significant number of circRNAs were deregulated in primary HSCs of mice with CCl 4 -induced HF, and the level of mmu_circ_0001682/mm9_circ_006613, named circPSD3 (from PSD3), markedly decreased in the CCl 4 -treated group. 21 To confirm the expression of circPSD3 in HF, we verified successful model establishment. Hematoxylin and eosin (H&E) staining revealed excessive inflammatory cell infiltration, hepatocyte necrosis, and formation of pseudolobules in the CCl 4 -treated group (Figure S1A).…”

Section: Aberrant Decrease In Circpsd3 Level In Mice With CCL 4 -Induced Hfmentioning

confidence: 95%

“…Concordantly, our previous study using RNA high-throughput sequencing technology showed that circRNAs were significantly altered in primary HSCs of mice with CCl 4 -induced HF and that circFBXW4 possessed anti-fibrotic potential, but there are some circRNAs that have undergone significant changes during the progression of HF whose functions are unknown. 21 In the present study, we aimed to investigate the role of another important circRNA in HF development. First, we found that the expression of mmu_circ_0001682/mm9_circ_006613/ circPSD3 (from exons 4-8 of Pleckstrin and Sec7 domain-containing 3 [PSD3] gene locus) was aberrantly reduced in primary HSCs of mice with CCl 4 -induced HF compared to that in the oil-treated group, consistent with our sequencing data.…”

Section: Introductionmentioning

confidence: 99%

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Circular RNA circPSD3 alleviates hepatic fibrogenesis by regulating the miR-92b-3p/Smad7 axis

Zhu

Chen

et al. 2021

Molecular Therapy - Nucleic Acids

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Recently, circular RNAs (circRNAs) have been frequently reported to be involved in hepatocellular carcinoma (HCC) development and progression. However, the role of circRNAs in hepatic fibrosis (HF) is still unclear. Our previous highthroughput screen revealed changes in many circRNAs in mice with carbon tetrachloride (CCl 4 )-induced HF. For instance, the expression of circPSD3, a circRNA derived from the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene, was considerably downregulated in primary hepatic stellate cells (HSCs) and liver tissues of mice with CCl 4 -induced HF compared to those in the vehicle group. In vivo overexpression of circPSD3 using AAV8-circPSD3 arrested the deterioration of CCl 4 -induced HF as indicated by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) content, liver hydroxyproline level, collagen deposition, and pro-fibrogenic gene and pro-inflammatory cytokine levels. Moreover, in vitro loss-of-function and gain-of-function analyses suggested that circPSD3 inhibited the activation and proliferation of HSCs. Mechanistically, circPSD3 served as a sponge for miR-92b-3p, subsequently promoting the expression of Smad7. In conclusion, our present findings reveal a novel mechanism by which circPSD3 alleviates hepatic fibrogenesis by targeting the miR-92b-3p/Smad7 axis, and they also indicate that circPSD3 may serve as a potential biomarker for HF.

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Circular RNA circFBXW4 suppresses hepatic fibrosis via targeting the miR-18b-3p/FBXW7 axis

Cited by 65 publications

References 41 publications

Circular RNA: an important player with multiple facets to regulate its parental gene expression

Circular RNA: an important player with multiple facets to regulate its parental gene expression

Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

Circular RNA circPSD3 alleviates hepatic fibrogenesis by regulating the miR-92b-3p/Smad7 axis

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