Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition

Lin, Yan; Koumba, Moussa Harouna; Qu, Suxuan; Wang, Dongxu; Lin, Lie‐Chwen

doi:10.1016/j.cellsig.2020.109707

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…1 B-D). Consistent with our previous work [ 17 ], the increased mRNA and protein levels of Nfatc3 were found in colons of UC-CRC mice (Fig. 1 E-F).…”

Section: Resultssupporting

confidence: 92%

“…Nfatc3 was highly expressed in the hypothalamus of high-fat diet-treated mice and induced a significant upregulation of inflammatory regulators [ 16 ]. Our previous study demonstrated that Nfatc3 promoted the inflammatory response and tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice [ 17 ]. However, the underlying mechanism by which Nfatc3 induces UC-CRC progression is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

et al. 2022

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Background Ulcerative colitis-associated colorectal cancer (UC-CRC) is an important complication of ulcerative colitis. Pou3f1 (POU class 3 homeobox 1) is a critical regulator for developmental events and cellular biological processes. However, the role of Pou3f1 in the development of UC-CRC is unclear. Methods In vivo, a UC-CRC mouse model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Body weight, colon length, mucosal damage, tumor formation, and survival rate were assessed to determine the progression of UC-CRC. Western blot, quantitative real-time PCR, ELISA, immunohistochemistry, immunofluorescence and TUNEL were performed to examine the severity of inflammation and tumorigenesis. In vitro, LPS-treated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were used to study the role of Pou3f1 in inflammation. ChIP and luciferase reporter assays were used to confirm the interaction between Nfatc3 and Pou3f1. Results Pou3f1 expression was increased in the colons of UC-CRC mice, and its inhibition attenuated mucosal injury, reduced colon tumorigenesis and increased survival ratio. Knockdown of Pou3f1 suppressed cell proliferation and increased cell death in colon tumors. Both the in vivo and in vitro results showed that Pou3f1 depletion reduced the production of proinflammation mediators. In addition, ChIP and luciferase reporter assays demonstrated that Nfatc3 directly bound with the Pou3f1 promoter to induce its expression. The effect of Nfatc3 on the inflammatory response in macrophages was suppressed by Pou3f1 knockdown. Conclusion Overall, it outlines that Pou3f1 mediates the role of Nfatc3 in regulating macrophage inflammation and carcinogenesis in UC-CRC development.

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“…1 B-D). Consistent with our previous work [ 17 ], the increased mRNA and protein levels of Nfatc3 were found in colons of UC-CRC mice (Fig. 1 E-F).…”

Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

et al. 2022

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“…Herein, we identified a novel circNFATC3, which might have the potential to bind with miR-23b-3p. Previous studies showed that NFATC3 can promote cancer stemness in oral/oropharyngeal squamous cell carcinomas 28 and inhibiting NFATC3 ameliorates colitis-associated colorectal cancer 29 . Herein, we found that circNFATC3 gave rise to a RNase R resistance in GC cells and harbored a co-localization with miR-23b-3p in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

RAI14 Regulated by circNFATC3/miR-23b-3p axis Facilitates Cell Growth and Invasion in Gastric Cancer

Yan

Zhang

et al. 2021

Cell Transplant

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Circular RNAs (circRNAs) have been proved to act crucial roles in multiple malignancies including gastric cancer (GC). Retinoic acid induced 14 (RAI14) acts as an oncogene in human cancers, but the underlying mechanisms by which RAI14 is regulated by circRNA/miRNA axis remain elusive. The clinical value of RAI14, miR-23b-3p and circNFATC3 was estimated by The Cancer Genome Atlas and fluorescence in situ hybridization. The interplay between miR-23b-3p and RAI14 or circNFATC3 was determined by qRT-PCR, Western blot, luciferase gene report and RIP assays. Biological function assays and a subcutaneous xenograft model were executed to unveil the role of circNFATC3/miR-23b-3p/RAI14 axis in GC cells. As a consequence, upregulation of RAI14 and circNFATC3 or downregulation of miR-23b-3p was associated with poor prognosis in patients with GC. Restored miR-23b-3p depressed cell proliferation, colony formation, and cell invasion by targeting RAI14, whereas RAI14 facilitated cell progression and reversed the anti-tumor effects of miR-23b-3p in GC cells. Then, circNFATC3 had a co-localization with miR-23b-3p in the cytoplasm in GC tissue cells and could act as a sponge of miR-23b-3p in GC cell line. Silencing of circNFATC3 inhibited cell growth and in vivo tumorigenesis by upregulating miR-23b-3p and downregulating RAI14. In conclusion, our findings indicated that RAI14 facilitated cell growth and invasion and was regulated by circNFATC3/miR-23b-3p axis in GC.

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“…NEATc3 might be implicated in regulating the transcription of various genes in immune cells and influencing the expression or function of cytokines, including interleukin‐4 (IL‐4) and interferon‐γ (IFN‐γ) 36 . Inhibition of NFATc3 attenuated the epithelial‐mesenchymal transition, decreased the levels of inflammatory cytokines and reduced the infiltration of neutrophils and macrophages in a dextran sulfate sodium‐induced colitis mouse model, 37 suggesting its potential regulatory role in inflammation and fibrosis. In the present study, NFATc3 was increased after hypoxia stimulation and participated in the regulatory roles of NEAT1 in hypoxia‐induced inflammation, apoptosis and fibrosis in alveolar epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

lncRNA NEAT1 promotes hypoxia‐induced inflammation and fibrosis of alveolar epithelial cells via targeting miR‐29a/NFATc3 axis

Zhang

Duan

et al. 2022

The Kaohsiung J of Med Scie

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The objective of the present study was to explore the function and mechanism of long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in pulmonary fibrosis (PF) progression. HPAEpic cells and A549 cells were exposed to hypoxic conditions to establish an in vitro model. Cell apoptosis was detected by TUNEL assay, and inflammatory cytokine levels were detected by ELISA. Gene and protein expression levels were identified by qRT-PCR and Western blot assays, respectively. The interaction among NEAT1, miR-29a, and NFATc3 was identified by dual-luciferase reporter and RNA pull-down assays. In hypoxia-treated cells, hypoxia markers (HIF-1α and HIF-2α), cytokines (TNF-α, IL-1β, and IL-6) and fibrotic markers (α-SMA, collagen I and collagen III) were significantly enhanced. Consistently, the expression levels of NEAT1 and NFATc3 were increased, but miR-29a was decreased in hypoxia-stimulated cells. Knockdown of NEAT1 significantly decreased cell apoptosis and the releases of TNF-α, IL-1β, and IL-6 as well as reduced the levels of α-SMA, collagen I, and collagen III. Moreover, NEAT1 positively regulated NFATc3 expression by directly targeting miR-29a. Functional experiments showed that the anti-apoptotic, anti-inflammatory, and anti-fibrotic effects mediated by NETA1 silencing were impeded by miR-29a inhibition or NFATc3 overexpression in hypoxiastimulated HPAEpic and A549 cells. Collectively, these data demonstrated that NEAT1 knockdown inhibited hypoxia-induced cell apoptosis, inflammation, and fibrosis by targeting the miR-29a/NFATc3 axis in PF, suggesting that NEAT1 might be a potential therapeutic target for relieving PF progression.

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Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition

Cited by 7 publications

References 49 publications

Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

RAI14 Regulated by circNFATC3/miR-23b-3p axis Facilitates Cell Growth and Invasion in Gastric Cancer

lncRNA NEAT1 promotes hypoxia‐induced inflammation and fibrosis of alveolar epithelial cells via targeting miR‐29a/NFATc3 axis

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