Overexpression of c-Met and CD44v6 Receptors Contributes to Autocrine TGF-β1 Signaling in Interstitial Lung Disease

Ghatak, Shibnath; Bogatkevich, Galina S.; Atnelishvili, Ilia; Akter, Tanjina; Feghali‐Bostwick, Carol; Hoffman, Stanley; Fresco, Victor M.; Fuchs, John C.; Visconti, Richard P.; Markwald, Roger R.; Padhye, Subhas B.; Silver, Richard M.; Hascall, Vincent C.; Misra, Suniti

doi:10.1074/jbc.m113.505065

Cited by 41 publications

(62 citation statements)

References 84 publications

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“…siRNA against TSIX or TGF‐β and control siRNA were purchased from Qiagen and Santa Cruz Biotechnology, respectively . After the transfection, cells were incubated for 96 h following the manufacture's protocol (http://www.eposters.net/pdfs/long-term-gene-silencing-in-mammalian-cells-using-sirna.pdf) and previous reports .…”

Section: Methodsmentioning

confidence: 99%

Long non‐coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization

Wang

Jinnin

Nakamura

et al. 2016

Experimental Dermatology

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Long non-coding RNAs (lncRNAs) are thought to have various functions other than RNA silencing. We tried to evaluate the expression of lncRNAs in patients with systemic sclerosis (SSc) and determined whether lncRNAs controls collagen expression in dermal fibroblasts. lncRNA expression was determined by real-time PCR and in situ hybridization. Protein and mRNA levels of collagen were analysed using immunoblotting and real-time PCR. We found TSIX, one of the lncRNAs, was overexpressed in SSc dermal fibroblasts both in vivo and in vitro, which was inhibited by the transfection of transforming growth factor (TGF)-β1 siRNA. TSIX siRNA reduced the mRNA expression of type I collagen in normal and SSc dermal fibroblasts, but not the levels of major disease-related cytokines. In addition, TSIX siRNA significantly reduced type I collagen mRNA stability, but not protein half-lives. Furthermore, we first investigated serum lncRNA levels in patients with SSc, and serum TSIX levels were significantly increased in SSc patients. TSIX is a new regulator of collagen expression which stabilizes the collagen mRNA. The upregulation of TSIX seen in SSc fibroblasts may result from activated endogenous TGF-β signalling and may play a role in the constitutive upregulation of collagen in these cells. Further studies on the regulatory mechanism of tissue fibrosis by lncRNAs in SSc skin lead to a better understanding of the pathogenesis, new diagnostic methods by their serum levels and new therapeutic approaches using siRNAs.

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Section: Methodsmentioning

confidence: 99%

Long non‐coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization

Wang

Jinnin

Nakamura

et al. 2016

Experimental Dermatology

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“…We have previously shown that expression of CD44V6 is directly related to fibrogenic function of human lung myofibroblasts (8). At the peak of lung collagen gene expression at day 14 after bleomycin lung injury in mice, the cells primarily responsible for fibrosis are activated myofibroblasts, as defined by expression of ␣-SMA.…”

Section: Myofibroblasts and Fibroblasts Of Pbs (Saline)-treated Lungsmentioning

confidence: 99%

“…Previous studies from our laboratory demonstrate a crucial role for TGF␤1 in controlling CD44V6 splicing in human lung fibrogenic fibroblast proliferation/activation through MAPK/ ERK1/2 (8). Despite its importance, however, the mechanisms underlying the sustained activity of MAPK/ERK1/2 signaling have remained less understood.…”

mentioning

confidence: 96%

“…A recent study provides evidence that hyaluronan synthase 2 (Has2), transgenically overexpressed by ␣-smooth-muscle actin (␣-SMA)-producing myofibroblasts, promotes a severe lung fibrotic phenotype in bleomycin-induced lung injury that also requires CD44, a receptor for hyaluronan (7). We have previously reported that lung myofibroblast activation by TGF␤1 is associated with the overexpression of CD44v6 and activation of MAPK/ERK1/2 (8). The EGR1 transcription factor has been implicated in mediating the fibrotic responses induced by TGF␤1 (9).…”

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confidence: 99%

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Transforming growth factor β1 (TGFβ1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts

Ghatak

Markwald

Hascall

et al. 2017

Journal of Biological Chemistry

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The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis. However, the cellular/molecular mechanisms that account for the fibroblast-myofibroblast differentiation/activation in idiopathic pulmonary fibrosis remain poorly understood. We investigated the functional role of hyaluronan receptor CD44V6 (CD44 containing variable exon 6 (v6)) for differentiation of lung fibroblast to myofibroblast phenotype. Increased hyaluronan synthesis and CD44 expression have been detected in numerous fibrotic organs. Previously, we found that the TGFβ1/CD44V6 pathway is important in lung myofibroblast collagen-1 and α-smooth-muscle actin synthesis. Because increased EGR1 (early growth response-1) expression has been shown to appear very early and nearly coincident with the expression of CD44V6 found after TGFβ1 treatment, we investigated the mechanism(s) of regulation of CD44V6 expression in lung fibroblasts by TGFβ1. TGFβ1-mediated CD44V6 up-regulation was initiated through EGR1 via ERK-regulated transcriptional activation. We showed that TGFβ1-induced CD44V6 expression is through EGR1-mediated (activator protein-1) activity and that the- and -binding sites in the promoter account for its responsiveness to TGFβ1 in lung fibroblasts. We also identified a positive-feedback loop in which ERK/EGR1 signaling promotes CD44V6 splicing and found that CD44V6 then sustains ERK signaling, which is important for activity in lung fibroblasts. Furthermore, we identified that-produced hyaluronan is required for CD44V6 and TGFβRI co-localization and subsequent CD44V6/ERK1/EGR1 signaling. These results demonstrate a novel positive-feedback loop that links the myofibroblast phenotype to TGFβ1-stimulated CD44V6/ERK/EGR1 signaling.

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“…The NSFbs were isolated and cultured as previously reported (Ghatak et al , 2013, 2014). Briefly, skin tissues were diced (approx.…”

Section: Cell Culturementioning

confidence: 99%

Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer

et al. 2014

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Inflammatory pathway plays an important role in tumor cell progression of colorectal cancers. Although colon cancer is considered as one of the leading causes of death worldwide, very few drugs are available for its effective treatment. Many studies have examined the effects of specific COX-2 and 5-LOX inhibitors on human colorectal cancer, but the role of isothiocyanates (ITSCs) as COX–LOX dual inhibitors engaged in hyaluronan–CD44 interaction has not been studied. In the present work, we report series of ITSC analogs incorporating bioisosteric thiosemicarbazone moiety. These inhibitors are effective against panel of human colon cancer cell lines including COX-2 positive HCA-7, HT-29 cells lines, and hyaluronan synthase-2 (Has2) enzyme over-expressing transformed intestinal epithelial Apc10.1Has2 cells. Specifically, our findings indicate that HA-CD44v6-mediated COX-2/5-LOX signaling mediate survivin production, which in turn, supports anti-apoptosis and chemo-resistance leading to colon cancer cell survival. The over-expression of CD44v6shRNA as well as ITSC treatment significantly decreases the survival of colon cancer cells. The present results thus offer an opportunity to evolve potent inhibitors of HA synthesis and CD44v6 pathway and thus underscoring the importance of the ITSC analogs as chemopreventive agents for targeting HA/CD44v6 pathway.

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Overexpression of c-Met and CD44v6 Receptors Contributes to Autocrine TGF-β1 Signaling in Interstitial Lung Disease

Cited by 41 publications

References 84 publications

Long non‐coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization

Long non‐coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization

Transforming growth factor β1 (TGFβ1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts

Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer

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