REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Li, Lei; Dang, Yongyan; Zhang, Jishen; Yan, Wangjun; Zhai, Wanli; Chen, Hui; Li, Ké; Lu, Tong; Gao, Xiao; Ali, Amjad; Ji, Lei; Jing, Tiantian; Jiang, Ziwei; Shi, Kaixuan; Yao, Liangfang; Song, Dianwen; Liu, Tielong; Yang, Xianghong; Yang, Cheng; Cai, Xiaopan; Xu, Wei; Huang, Quan; He, Jia; Liu, Jian; Chen, Tenghui; Moses, Robb E.; Fu, Junjiang; Xiao, Jianru; Li, Xiaotao

doi:10.1038/ncomms7875

Cited by 69 publications

(78 citation statements)

References 43 publications

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“…This finding is in line with the critical role of β -catenin inactivation in a series of studies. 42, 43 It is also consistent with our previous study illustrating the inhibitory effect of miR-27a/PPAR γ axis in renal tubulointerstitial fibrosis in DN. 44 In glomerular mesangial cells, miR-27a has been reported to induce progression of DN by targeting PPAR γ .…”

Section: Discussionsupporting

confidence: 91%

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

et al. 2017

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Podocyte injury has a pivotal role in the pathogenesis of diabetic nephropathy (DN). MicroRNA-27a (miR-27a), peroxisome proliferator-activated receptor γ (PPARγ) and β-catenin pathways have been involved in the pathogenesis of DN. Herein, we asked whether miR-27a mediates podocyte injury through PPARγ/β-catenin signaling in DN. The functional relevance of miR-27a, PPARγ and β-catenin were investigated in cultured podocytes and glomeruli of diabetic rats and patients using in vitro and in vivo approaches. Podocyte injury was assessed by migration, invasion and apoptosis assay. Biological parameters were analyzed using enzyme-linked immunosorbent assay. We found that high glucose stimulated miR-27a expression, which, by negatively targeting PPARγ, activated β-catenin signaling as evidenced by upregulation of β-catenin target genes, snail1 and α-smooth muscle actin (α-SMA) and downregulation of podocyte-specific markers podocin and synaptopodin. These changes caused podocyte injury as demonstrated by increased podocyte mesenchymal transition, disrupted podocyte architectural integrity and increased podocyte apoptosis. Furthermore, we provide evidence that miR-27a contributed to unfavorable renal function and increased podocyte injury in diabetic rats. Notably, miR-27a exhibited clinical and biological relevance as it was linked to elevated serum creatinine, proteinuria and reduced creatinine clearance rate. In addition, miR-27a upregulation and activation of PPARγ/β-catenin signaling were verified in renal biopsy samples from DN patients. We propose a novel role of the miR-27a/PPARγ/β-catenin axis in fostering the progression toward more deteriorated podocyte injury in DN. Targeting miR-27a could be a potential therapeutic approach for DN.

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Section: Discussionsupporting

confidence: 91%

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

et al. 2017

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“…To evaluate the role of REGγ during melanoma progression, REGγ was silenced with specific shRNA as described in A375 and SK‐MEL‐28 human melanoma cells. We found that cell growth was significantly decreased in ShR (REGγ knockdown) cells by MTT assay (Figure A, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As GSK‐3β has been demonstrated as a target protein of REGγ‐proteasome system in our previous non‐melanoma skin cancer model, this phenomenon was investigated in melanoma cells. We found that REGγ knockdown increased the level of total GSK‐3β with concurrent decrease in β‐catenin in A375 and SK‐MEL‐28 cells (Figure A).…”

Section: Resultsmentioning

confidence: 99%

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REGγ accelerates melanoma formation by regulating Wnt/β‐catenin signalling pathway

Chen

Gao

Sun

et al. 2017

Experimental Dermatology

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It has been reported that the proteasome activator REGγ is associated with multiple oncogenic pathways in human cancers. However, the role of REGγ in the development of melanoma and the underlying mechanisms remain unclear. In this study, we attempted to investigate the effects of REGγ on human melanoma cell proliferation in vitro and in vivo. We demonstrated that knockdown of REGγ inhibited melanoma cell growth and arrested melanoma cell at G1 phase. Furthermore, depletion of REGγ also inhibited the xenograft growth of human melanoma. Mechanistically, REGγ activates Wnt/β-catenin signal pathway by degrading GSK-3β in melanoma cell lines and mouse models. Transient knockdown of β-catenin effectively blocked cell proliferation in REGγ wild-type melanoma cells. In human melanoma samples, REGγ was overexpressed and positively correlated with β-catenin levels. This study demonstrates that REGγ is a central molecule in the development of melanoma by regulating Wnt/β-catenin pathway. This suggests that targeting REGγ could be an alternative therapeutic approach for melanoma.

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“…PSME3-KO mice were described previously (Li et al, 2015). All the protocols were approved by East China Normal University.…”

Section: Methodsmentioning

confidence: 99%

The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens

et al. 2016

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SUMMARY The NF-κB pathway plays important roles in immune responses. Although its regulation has been extensively studied, here, we report an unknown feedforward mechanism for the regulation of this pathway by Toll-like receptor (TLR) ligands in macrophages. During bacterial infections, TLR ligands upregulate the expression of the 11S proteasome subunit PSME3 via NF-κB-mediated transcription in macrophages. PSME3, in turn, enhances the transcriptional activity of NF-κB by directly binding to and destabilizing KLF2, a negative regulator of NF-κB transcriptional activity. Consistent with this positive role of PSME3 in NF-κB regulation and importance of the NF-κB pathway in host defense against bacterial infections, the lack of PSME3 in hematopoietic cells renders the hosts more susceptible to bacterial infections, accompanied by increased bacterial burdens in host tissues. Thus, this study identifies a substrate for PSME3 and elucidates a proteolysis-dependent, but ubiquitin-independent, mechanism for NF-κB regulation that is important for host defense and innate immunity.

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REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Cited by 69 publications

References 43 publications

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

REGγ accelerates melanoma formation by regulating Wnt/β‐catenin signalling pathway

The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens

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