Transmembrane protein 88 attenuates liver fibrosis by promoting apoptosis and reversion of activated hepatic stellate cells

Cai, Shuang-Peng; Cheng, Xiaoyu; Chen, Peijie; Pan, Xue‐Yin; Xu, Tao; Huang, Cheng; Meng, Xiao‐Ming; Li, Jun

doi:10.1016/j.molimm.2016.11.002

Cited by 28 publications

(16 citation statements)

References 29 publications

(32 reference statements)

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“…Primary HSCs were isolated from mice as previously described 28 . Liver of mice was digested with Collagenase IV (Sigma-Aldrich, St. Louis, USA) and Pronase E (Sigma-Aldrich, St. Louis, USA) dissolved in PB buffer.…”

Section: Methodsmentioning

confidence: 99%

Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

Chen

et al. 2018

Cell Death Dis

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Hepatic myofibroblasts, activated hepatic stellate cells (HSCs), are the main cell type of extracellular matrix (ECM) deposition during hepatic fibrosis. Aberrant DNA methylation-regulated HSCs activation in liver fibrogenesis has been reported, but the functional roles and mechanisms of DNA methylation in hepatic fibrosis remain to be elucidated. In the present study, reduced representation bisulfite sequencing (RRBS) analysis of primary HSCs revealed hypermethylation patterns in hepatic fibrosis. Interestingly, we found SAD1/UNC84 domain protein-2 (SUN2) gene hypermethylation at CpG sites during liver fibrogenesis in mice with CCl4-induced hepatic fibrosis, which was accompanied by low expression of SUN2. In vivo overexpression of SUN2 following adeno-associated virus-9 (AAV9) administration inhibited CCl4-induced liver injury and reduced fibrogenesis marker expression. Consistently, in vitro experiments showed that enforced expression of SUN2 suppressed HSCs activation and exerted anti-fibrogenesis effects in TGF-β1-activated HSC-T6 cells. In addition, the signaling mechanisms related to SUN2 expression were investigated in vivo and in vitro. Methyltransferase-3b (DNMT3b) is the principal regulator of SUN2 expression. Mechanistically, inhibition of protein kinase B (AKT) phosphorylation may be a crucial pathway for SUN2-mediated HSCs activation. In conclusion, these findings provide substantial new insights into SUN2 in hepatic fibrosis.

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Section: Methodsmentioning

confidence: 99%

Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

Chen

et al. 2018

Cell Death Dis

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“…TMEM88 expression is decreased in the human liver fibrotic tissues. In vitro assays prove that TMEM88 inhibits activation and proliferation of hepatic stellate cells (HSCs) by blocking Wnt/β-catenin pathway, and promotes the activated HSCs apoptosis by initiating Bcl-2/Bax/Caspase3 pathway [14]. TMEM88 was also found to be downregulated in renal fibrotic tissues and TGF-β1-treated HK2 cells.…”

Section: Discussionmentioning

confidence: 98%

“…attenuates liver fibrosis via regulating Wnt/β-catenin and Bcl-2/Bax/Caspase3 signaling pathways [14]. Zhao et al [15] reported that TMEM88 inhibits hyper-proliferation and migration of fibroblasts and suppresses excess ECM deposition in TGF-β1-stimulated keloid-derived fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

TMEM88 inhibits TGF-β1-induced-extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) program in human pleural mesothelial cells through modulating TGF-β1/Smad pathway

Sun

Niu²,

et al. 2020

Preprint

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Pleural fibrosis is an irreversible pathological process occurred in the development of several lung diseases. TMEM88 is a member of transmembrane (TMEM) family and has been found to be involved in the regulation of fibrogenesis. However, the role of TMEM88 in pleural fibrosis remains unknown. In this study, we aimed to explore the role of TMEM88 in pleural fibrosis in vitro using TGF-β1-induced human pleural mesothelial cell line MeT-5A cells. Our results showed that the expression levels of TMEM88 were downregulated in pleural fibrosis tissues and TGF-β1-treated Met-5A cells. Overexpression of TMEM88 inhibited the proliferation of Met-5A cells under TGF-β1 stimulation. In addition, TMEM88 overexpression prevented TGF-β1-induced extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) in Met-5A cells with decreased expression levels of Col I and fibronectin, increased levels of cytokeratin-8 and E-cadherin, as well as decreased levels of vimentin and α-SMA. Furthermore, overexpression of TMEM88 inhibited the expression of TGF-β receptor I (TβRI) and TβRII and suppressed the phosphorylation of Smad2 and Smad3 in Met-5A cells. In conclusion, these results indicated that TMEM88 exhibited an anti-fibrotic activity in pleural fibrosis via inhibiting the activation of TGF-β1/Smad signaling pathway.

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“…TMEM88 inhibits Wnt/β-Catenin signaling through interaction with the Wnt pathway factor Dishevelled ( DVLS ) 14 . Therefore, the hypermethylation of the TMEM88 gene may inhibit its function as a negative modulator of Wnt/β-Catenin signaling, which results in the constitutive activation of this signal pathway in NSCLC 30 . This may explain why the hypermethylation of TMEM88 in NSCLC is associated with an unfavorable prognosis.…”

Section: Discussionmentioning

confidence: 99%

Promoter methylation of Wnt/β-Catenin signal inhibitor TMEM88 is associated with unfavorable prognosis of non-small cell lung cancer

Feng

et al. 2017

Cancer Biology & Medicine

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Objective: Recent research has indicated that altered promoter methylation of oncogenes and tumor suppressor genes is an important mechanism in lung cancer development and progression. In this study, we investigated the association between promoter methylation of TMEM88, a possible inhibitor of the Wnt/β-Catenin signaling, and the survival of patients with non-small cell lung cancer (NSCLC). Methods: Twelve pairs of tumor and adjacent non-tumor samples were used for microarray analyses of DNA methylation and gene expression. For validation, more than two hundred additional samples were analyzed for methylation using bisulfite pyrosequencing and for gene expression using qRT-PCR. Then the cell function were tested by wound healing, transwell, CCK8 and cell cycle assay. Results: Our analysis of patient specimens showed that TMEM88 methylation was higher in NSCLC tumors (82.2% ± 10.3, P < 0.01) compared with the adjacent normal tissues (65.9% ± 7.2). The survival analysis revealed that patients with high TMEM88 methylation had a shorter overall survival (46 months) compared with patients with low TMEM88 methylation (>56 months;P=0.021). In addition, we found that demethylation treatment could inhibit tumor cell proliferation, migration, and invasion, which was supportive of an association between methylation and survival. Conclusions: Based on these consistent observations, we concluded that TMEM88 may play an important role in NSCLC progression and that promoter methylation of TMEM88 may serve as a biomarker for NSCLC prognosis and treatment.

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Transmembrane protein 88 attenuates liver fibrosis by promoting apoptosis and reversion of activated hepatic stellate cells

Cited by 28 publications

References 29 publications

Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

TMEM88 inhibits TGF-β1-induced-extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) program in human pleural mesothelial cells through modulating TGF-β1/Smad pathway

Promoter methylation of Wnt/β-Catenin signal inhibitor TMEM88 is associated with unfavorable prognosis of non-small cell lung cancer

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