Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

Liu, Gang; Cooley, Marion A.; Jarnicki, Andrew G.; Borghuis, Theo; Nair, Prema M.; Tjin, Gavin; Hsu, Alan; Haw, Tatt Jhong; Fricker, Michael; Harrison, Celeste L.; Jones, Bernard Edward; Hansbro, Philip M.; Wark, Peter; Horvat, Jay C.; Argraves, W. Scott; Oliver, Brian G.; Knight, Darryl A.; Burgess, Janette K.

doi:10.1172/jci.insight.124529

Cited by 52 publications

(56 citation statements)

References 72 publications

(111 reference statements)

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“…To understand the mechanism of increased ELN in CRC, we measure ELN gene expression in cancer cells after TGF-β stimulation. TGF-β is a fibrotic cytokine that induces ECM proteins in many diseases [24]. However, the level of ELN gene expression does not change between cells treated with TGF-β recombinant protein and controls, indicating TGF-β is not involved in the induction of ELN expression in CRC.…”

Section: Discussionmentioning

confidence: 99%

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Elastin is a key factor of tumor development in colorectal cancer

Jiang

et al. 2020

BMC Cancer

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Background: Colorectal cancer (CRC) is the most common cancer and a leading cause of death worldwide. Extracellular matrix (ECM) proteins regulate tumor growth and development in CRC. Elastin (ELN) is a component of ECM proteins involved in the tumor microenvironment. However, the role of ELN in CRC remains unclear. Methods: In this study, we analyzed ELN gene expression in tumors from CRC patients and adjacent non-tumor colon tissues and healthy controls from two existing microarray datasets. ELN protein was measured in human normal colon cells and colon cancer epithelial cells and tumor development was assessed in colon epithelial cells cultured in medium with or without ELN peptide on plates coated with ELN recombinant protein. Control plates were coated with PBS only. Results: We found ELN gene expression was increased in tumors from CRC patients compared to adjacent nontumor tissues and healthy controls. ELN protein was increased in cancer cells compared to normal colon epithelial cells. Transforming growth factor beta (TGF-β) was a key cytokine to induce production of ECM proteins, but it did not induce ELN expression in colon cancer cells. Matrix metalloproteinase 9 (MMP9) gene expression was increased, but that of MMP12 (elastase) did not change between CRC patients and control. Tissue inhibitor of metalloproteinases 3 (TIMP3) gene expression was decreased in colon tissues from CRC patients compared to healthy controls. However, MMP9, MMP12 and TIMP3 proteins were increased in colon cancer cells. ELN recombinant protein increased proliferation and wound healing in colon cancer epithelial cells. This had further increased in cancer cells incubated in plates coated with recombinant ELN coated plate and in culture media containing ELN peptide. A potential mechanism was that ELN induced epithelial mesenchymal transition with increased alpha-smooth muscle actin and vimentin proteins but decreased E-cadherin protein. Tumor necrosis factor alpha (TNF) mRNA was also increased in CRC patients compared to controls. ELN recombinant protein induced further increases in TNF protein in mouse bone marrow derived macrophages after lipopolysaccharide stimulation. Conclusions: These data suggest ELN regulates tumor development and the microenvironment in CRC.

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Section: Discussionmentioning

confidence: 99%

“…Some blots were cut based on molecular weight and some blots were stripped only once for housekeeping protein. Densitometry analysis was performed relative to the housekeeping protein β-actin using ImageJ (NIH, Bethesda, USA) as previously described [23,24].…”

Section: Immunoblotmentioning

confidence: 99%

Elastin is a key factor of tumor development in colorectal cancer

Jiang

et al. 2020

BMC Cancer

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“…20 This chronic activation is possibly related to oxidative stress, inflammatory reactions, aging, and immunity. [21][22][23][24] Currently, there is no effective drug for IPF, and the optimal treatment is lung transplantation. MSCs are a type of mesodermal adult stem cell that are widely distributed in connective tissues and organ stroma.…”

Section: Discussionmentioning

confidence: 99%

Curcumin protects murine lung mesenchymal stem cells from H₂O₂ by modulating the Akt/Nrf2/HO-1 pathway

Zhang

Lan

et al. 2020

J Int Med Res

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Objectives: Oxidative stress within the idiopathic pulmonary fibrosis microenvironment decreases the survival of lung mesenchymal stem cells (LMSCs), resulting in disease progression. Herein, the effects of curcumin (CUR) against hydrogen peroxide (H 2 O 2 )-mediated damage to murine LMSCs were examined. Methods: Apoptosis, reactive oxygen species, and mitochondrial membrane potential were detected by flow cytometry. Protein levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated x (Bax), cleaved caspase-3, protein kinase B (PKB/Akt), phosphorylated-Akt, nuclear factor erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were evaluated by western blot analysis. Results: Apoptosis rates in the 2.5, 5, and 10 mM CUR groups were 23.27% AE 0.31%, 14.87% AE 0.41%, and 6.47% AE 0.50%, respectively, all of which were lower than in the H 2 O 2 group (24.46% AE 1.35%). Reactive oxygen species levels were decreased, while mitochondrial membrane potential levels were increased in concentration-dependent manners in the CUR groups compared with the H 2 O 2 group. Compared with the H 2 O 2 group, all CUR groups showed reduced cleaved caspase-3 expression, increased Nrf2 and HO-1 expression, and increased Bcl-2/Bax and p-Akt/Akt ratios. Conclusions: The protective effects of CUR against H 2 O 2 -mediated damage in murine LMSCs may be mediated through the Akt/Nrf2/HO-1 signaling pathway.

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“…TGF-β1 which has been identi ed as the key pro brogenic cytokine could regulate EMT process through multiple signaling pathways [54][55][56], such as Smad and p38 MAPK. Canonical Smad signaling pathway is considered to be the most important pathway in EMT and most of the TGF-β1-induced EMT appears to be dependent on this signaling pathway [36,57].…”

Section: Discussionmentioning

confidence: 99%

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Xue

et al. 2020

Preprint

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Background: Renal interstitial fibrosis (RIF) is one of the main poor prognostic factors of lupus nephritis (LN). Here, we tested whether iguratimod could inhibit RIF in LN. Methods: MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney was evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor β1 (TGF-β1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3 and p-p38 MAPK in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence. Results: In MRL/lpr mice, iguratimod eased the renal interstitial deposition of collagen fibers, further confirmed by decreased expression of COL-I after iguratimod treatment. Moreover, upstream pathological processes of RIF, including IgG deposition along the tubular basement membrane, infiltration of inflammatory cells into renal interstitium and tubular injury, were also prevented effectively by iguratimod treatment. Furthermore, iguratimod suppressed the expression of FSP-1 and raised the expression of E-cadherin in renal tubular epithelial cells, suggesting that iguratimod reversed the process of tubular epithelial-to-mesenchymal transition (EMT). In HK2 cells induced by TGF-β1, co-treatment with iguratimod not only reversed cellular morphologic change, but also prevented down-regulation of E-cadherin and up-regulation of fibronectin. Finally, iguratimod blocked TGF-β1-induced phosphorylation of Smad2/3 and p38 MAPK in HK2 cells. Conclusions: Our results suggest that iguratimod shows an inhibitory effect on the progress of RIF in vivo and in vitro, so iguratimod may be a potential drug for the treatment of RIF in LN.

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Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

Cited by 52 publications

References 72 publications

Elastin is a key factor of tumor development in colorectal cancer

Elastin is a key factor of tumor development in colorectal cancer

Curcumin protects murine lung mesenchymal stem cells from H₂O₂ by modulating the Akt/Nrf2/HO-1 pathway

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

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Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

Cited by 52 publications

References 72 publications

Elastin is a key factor of tumor development in colorectal cancer

Elastin is a key factor of tumor development in colorectal cancer

Curcumin protects murine lung mesenchymal stem cells from H2O2 by modulating the Akt/Nrf2/HO-1 pathway

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

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Curcumin protects murine lung mesenchymal stem cells from H₂O₂ by modulating the Akt/Nrf2/HO-1 pathway