TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice

Thiele, Nina; Wirth, Jan; Steins, David; Koop, Anja; Ittrich, Harald; Lohse, Ansgar W.; Kluwe, Johannes

doi:10.1038/s41598-017-00671-1

Cited by 49 publications

(30 citation statements)

References 33 publications

(46 reference statements)

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“…58 TIMPs are well-studied proteins in liver fibrosis, and their expression is in inverse correlation to that in the disease stage. 59 Previous reports suggest that TIMP-1 overexpression inhibits MMPs activity and leads to a decrease in clearance of ECM. 60 The interaction between activated hepatic myofibroblasts and Kupffer cells results in increased TIMP-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis

Kumar

Luo

et al. 2018

Molecular Therapy

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Trans-differentiation of quiescent hepatic stellate cells (HSCs) into active myofibroblasts secretes excess amounts of extracellular matrix (ECM) proteins. miR-29b1 has the potential to treat liver fibrosis, because it targets several profibrotic genes. We previously demonstrated that miR-29b1 and the hedgehog (Hh) pathway inhibitor GDC-0449 could, together, inhibit the activation of HSCs and ECM production in common bile-duct-ligated (CBDL) mice. Herein, we determined the effect of chemical modifications of miR-29b1 on its stability, immunogenicity, and Argonaute-2 (Ago2) loading in vitro, after modifying its antisense strand with phosphorothioate (PS-miR-29b1), 2 0-O-methyl-phosphorothioate (OMe-miR-29b1), locked nucleic acid (LNA-miR-29b1), and N,N'-diethyl-4-(4-nitronaphthalen-1-ylazo)-phenylamine (ZEN-miR-29b1). Chemical modifications significantly improved stability of miR-29b1 in 50% FBS. Among all the modified miRNAs tested, OMe-PS-miR-29b1 showed the highest stability with low immunogenicity, without the loss of efficacy in vitro. Therefore, OMe-PS-miR-29b1 was complexed with poly(ethylene glycol)-block-poly(2methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-grafttetraethylenepentamine (mPEG-b-PCC-g-DC-g-TEPA) cationic micelles, and anti-fibrotic efficacy was evaluated in CBDL mice. There was a significant improvement in liver histology and decrease in the levels of injury markers. Further, mRNA/protein levels of collagen, a-SMA, and TIMP-1 were significantly lower for the OMe-PS-miR-29b1-loaded micelles compared to miR-29b1-loaded micelles. In conclusion, micellar delivery of OMe-PS-miR-29b1 is a promising strategy to treat liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis

Kumar

Luo

et al. 2018

Molecular Therapy

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“…The second profibrogenic protein is TIMP-1, which prevents dissolving or dissociation of the ECM via the inhibition of matrix metalloproteinases and hence promote fibrosis (Yoshiji et al, 2000). However, a recent report (Thiele et al, 2017) demonstrated only association and not the promotion of liver fibrosis by TIMP-1. HIF-1α and mTOR were found to increase these profibrogenic biomarkers and hence promote fibrosis (Hu et al, 2017;Zhao et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers in thioacetamide‐induced hepatic tissue alterations

Al‐Hashem

Al‐Humayed

Amin

et al. 2018

Journal Cellular Physiology

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The potential inhibitory effect of the antidiabetic and anti‐inflammatory drug, metformin on thioacetamide (TAA)‐induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)–hypoxia‐inducible factor‐1α (HIF‐1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA‐induced HIF‐1α, mTOR, the profibrogenic biomarker α‐smooth muscle actin, tissue inhibitor of metalloproteinases‐1, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF‐1α) and the serum levels of TNF‐α ( r = 0.797), IL‐6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA‐induced hepatic injuries in rats, which is associated with the inhibition of mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans.

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“…Previous studies demonstrated that Type IV collagenases are implicated in tumor cell invasion and migration processes (22,23). MMPs are controlled by endogenous tissue specific inhibitors, also known as tissue inhibitors of metalloproteinases (TIMPs) (24). TIMP1 can inhibit tumor progression by suppressing MMP9-mediated release of vascular endothelial growth factor from the matrix.…”

Section: Discussionmentioning

confidence: 99%

Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

2018

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Colon cancer is characterized by invasion and migration. DNA methylation of CpG islands in tumor suppressor genes is considered to be an epigenetic mechanism underlying cancer development. Epigenetic silencing of a gene may be reversed by drugs, including genistein. The present study aimed to determine the effect of genistein on Wnt inhibitory factor 1 (WIF1) and invasion, and migration of colon cancer cells. The viability of HT29 colon cancer cells was suppressed by genistein in a dose dependent manner. Following 72 h of treatment with 10, 20 and 60 µmol/l genistein, increased demethylation of WIF1 was induced in a dose‑dependent manner. Additionally, the invasive/migratory abilities of cells treated with genistein decreased in a dose‑dependent manner. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were performed to identify the mRNA and protein expression levels of invasion/migration‑associated factors. Following treatment with genistein, matrix metalloproteinase (MMP) 2 and MMP9 expression levels decreased, whereas the expression of metalloproteinase inhibitor 1 and E‑cadherin increased significantly. In addition, the expression levels of proto‑oncogene Wnt‑1 (Wnt‑1)/β‑catenin pathway‑associated factors, β‑catenin, c‑Myc proto‑oncogene protein and cyclin D1 decreased in a dose‑dependent manner following treatment with genistein. The invasive/migratory abilities of cells transfected with WIF1‑small interfering (si) RNA, and those transfected with WIF1‑siRNA and treated with genistein, increased notably compared with the control group. The present study demonstrated that genistein was able to inhibit the cell invasion and migration of colon cancer cells by inducing demethylation, and recovering the activity of WIF1 by altering the expression of invasion‑associated factors, and components of the Wnt signaling pathway.

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TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice

Cited by 49 publications

References 33 publications

Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis

Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis

Metformin inhibits mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers in thioacetamide‐induced hepatic tissue alterations

Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

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