Functional crosstalk between myeloid Foxo1–β-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response

Li, Changyong; Sheng, Mingwei; Lin, Yuanbang; Xu, Dongwei; Tian, Yizhu; Zhan, Yongqiang; Jiang, Longfeng; Coito, Ana J.; Busuttil, Ronald W.; Farmer, Douglas G.; Kupiec‐Weglinski, Jerzy W.; Ke, Bibo

doi:10.1038/s41418-020-00695-7

Cited by 48 publications

(57 citation statements)

References 53 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MET, AM25C, MROH9, MYEOV, FAM111B, Y6D, and PPP2R3A were highly expressed in the high-risk group, indicating that these genes may be related to the oncology process for patients with PAAD, and they seemed to be cancerpromoting genes. The results of the abovementioned genes provide some insights for further research, but conclusive evidence that they are involved in the expression of specific transcription factors related to necroptosis regulation, such as USP22, CDK9, and Foxo1 [24][25][26] is lacking, which requires further investigation. CASKIN2, TLE2, USP20, SPRN, ARSG, MIR106B, and MIR98 were considered to be substantially expressed in the low-risk group, suggesting that these genes may be PAAD tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma

Huang

Cai

et al. 2022

Aging

View full text Add to dashboard Cite

Pancreatic adenocarcinoma (PAAD) is a deadly digestive system tumor with a poor prognosis. Recently, necroptosis has been considered as a type of inflammatory programmed cell death. However, the expression of necroptosis-related genes (NRGs) in PAAD and their associations with prognosis remain unclear. NRGs' prediction potential in PAAD samples from The TCGA and GEO datasets was investigated. The prediction model was constructed using Lasso regression. Co-expression analysis showed that gene expression was closely related to necroptosis. NRGs were shown to be somewhat overexpressed in high-risk people even when no other clinical symptoms were present, indicating that they may be utilized in a model to predict PAAD prognosis. GSEA showed immunological and tumor-related pathways in the high-risk group. Based on the findings, immune function and m6A genes differ significantly between the low-risk and high-risk groups. MET, AM25C, MROH9, MYEOV, FAM111B, Y6D, and PPP2R3A might be related to the oncology process for PAAD patients. Moreover, CASKIN2, TLE2, USP20, SPRN, ARSG, MIR106B, and MIR98 might be associated with low-risk patients with PAAD. NRGs and the relationship of the immune function, immune checkpoints, and m6A gene expression with NRGs in PAAD may be considered as potential therapeutic targets that should be further studied.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma

Huang

Cai

et al. 2022

Aging

View full text Add to dashboard Cite

show abstract

“…A recent study demonstrated that myeloid-specific Foxo1-deficient promoted β-catenin-mediated Gli1/Snail signaling activation, and alleviated oxidative stress-induced hepatic injury with decreased accumulation of macrophage/neutrophil in liver IRI. Mechanism analysis showed that Foxo1 directly bounded to endogenous β-catenin in the nucleus, and Foxo1–β-catenin complex in macrophages reduced β-catenin–TCF4 binding via LPS [ 39 ]. Then, we investigated the relationship between the ATF6–CHOP axis and β-catenin signaling in the modulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling

Yang

Wang

et al. 2022

Cell Death Discov.

View full text Add to dashboard Cite

Although hyperglycemia has been documented as an unfavorable element that can further induce liver ischemia–reperfusion injury (IRI), the related molecular mechanisms remain to be clearly elaborated. This study investigated the effective manner of endoplasmic reticulum (ER) stress signaling in hyperglycemia-exacerbated liver IRI. Here we demonstrated that in the liver tissues and Kupffer cells (KCs) of DM patients and STZ-induced hyperglycemic mice, the ER stress-ATF6-CHOP signaling pathway is activated. TLR4-mediated pro-inflammatory activation was greatly attenuated by the addition of 4-phenylbutyrate (PBA), one common ER stress inhibitor. The liver IRI in hyperglycemic mice was also significantly reduced after PBA treatment. In addition, deficiency of CHOP (CHOP−/−) obviously alleviates the hepatic IRI, and pro-inflammatory effects deteriorated by hyperglycemia. In hyperglycemic mice, β-catenin expression was suppressed while the ATF6-CHOP signal was activated. In the liver tissues of PBA-treated or CHOP−/− hyperglycemic mice, the expression of β-catenin was restored. Furthermore, CHOP deficiency can induce protection against hyperglycemia-related liver IRI, which was disrupted by the knockdown of β-catenin will cause this protection to disappear. High glucose (HG) treatment stimulated ATF6-CHOP signaling, reduced cellular β-catenin accumulation, and promoted the TLR4-related inflammation of BMDMs. But the above effects were partially rescued in BMDMs with CHOP deficiency or by PBA treatment. In BMDMs cultured in HG conditions, the anti-inflammatory functions of CHOP−/− were destroyed by the knockdown of β-catenin. Finally, chimeric mice carrying WT or CHOP−/− BMDMs by bone marrow transplantation were adopted to verify the above conclusion. The current study suggested that hyperglycemia could trigger ER stress-ATF6-CHOP axis, inhibit β-catenin activation, accelerate inflammation, and deteriorate liver IRI, thus providing the treatment potential for management of sterile liver inflammation in DM patients.

show abstract

“…Activation of β-catenin signaling promotes endothelial cell programmed necrosis under conditions of hyperlipidemia [33]. In addition, activated β-catenin can enter the nucleus and bind to Foxo1 to activate Foxo1 and increase hepatocyte necroptosis [21]. Our data show that serpina3c knockdown activated β-catenin/Foxo1 and promoted necroptosis under conditions of lipotoxicity.…”

Section: Discussionmentioning

confidence: 63%

“…Moreover, the total protein and nuclear protein levels of β-catenin were signi cantly upregulated in serpina3c-knockdown cells, and these effects were reversed by serpina3c overexpression (Figure 5B and 5C). The regulation of forkhead box o1 (Foxo1) by β-catenin is particularly important in reducing liver necroptosis [21]. β-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Foxo1 to promote necroptosis under oxidative stress.…”

Section: The Effect Of Serpina3c On β-Catenin and Foxo1 Expression And Nuclear Transfermentioning

confidence: 99%

Serpina3c Deficiency Induced Necroptosis Promotes Non-Alcoholic Steatohepatitis Through β-Catenin/Foxo1/TLR4 Signaling

Qian¹,

Ji²,

Jiang³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Hepatocyte death and liver inﬂammation have been recognized as central characteristics of nonalcoholic steatohepatitis (NASH); however, the underlying molecular mechanism remains elusive. The aim of this study is to determine the precise role of serpina3c in the progression of NASH.Methods: Male Apoe-/-/serpina3c-/- double knockout (DKO) and Apoe-/- mice were fed a high-fat diet (HFD) for 12 weeks to induce NASH. Several markers of steatosis and inﬂammation were evaluated. In vitro cell models induced by palmitic acid (PA) treatment were used to evaluate the beneficial effect of serpina3c on necroptosis and the underlying molecular mechanism.Results: Compared with Apoe-/- mice, DKO mice exhibited a signiﬁcantly exacerbated NASH phenotype that included hepatic steatosis, inflammation, ﬁbrosis and liver damage, and increased hepatic triglyceride contents. We also indicated that the expression of the receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like (MLKL) was increased in DKO mice. Our results found that serpina3c knockdown promoted necroptosis and lipid droplet formation under conditions of lipotoxicity in vitro. However, these phenomena were reversed by the overexpression of serpina3c. Mechanistically, downregulation of serpina3c expression promoted Foxo1 and β-catenin expression, and Foxo1 and β-catenin colocalized in the nucleus under conditions of lipotoxicity, consequently upregulating the expression of Toll-like receptor4 (TLR4). However, disruption of the Foxo1-β/catenin by Foxo1 and β-catenin inhibitors decreased TLR4 expression and ameliorated hepatic necroptosis in vitro.Conclusion: Serpina3c plays a protective role against the progression of NASH by inhibiting necroptosis. Serpina3c, a Wnt/β-catenin inhibitor, inhibits necroptosis via β-catenin/Foxo1 by inhibiting TLR4 expression.

show abstract

Functional crosstalk between myeloid Foxo1–β-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response

Cited by 48 publications

References 53 publications

Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma

Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma

Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling

Serpina3c Deficiency Induced Necroptosis Promotes Non-Alcoholic Steatohepatitis Through β-Catenin/Foxo1/TLR4 Signaling

Contact Info

Product

Resources

About