Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

Zhou, Yang; Lee, Jae-Young; Cho, Won‐Kyung; Kang, Min Jong; Koff, Jonathan L.; Yoon, Pyeong-Oh; Chae, Jeiwook; Park, Han-Oh; Elias, Jack A.; Lee, Chang-Min

doi:10.1074/jbc.m112.356824

Cited by 127 publications

(143 citation statements)

References 47 publications

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“…Consistent with this point, our AREG staining in vivo did show a predominant apical expression, similar to our BALF data, but also indicated subepithelial expression, as well as within SMA-positive areas, as seen in the larger airways. Further study of the in vivo importance of AREG and EGFR signaling in the context of our BO model should help to better elucidate its role and function in fibrotic lung disease (16).…”

Section: Discussionmentioning

confidence: 99%

Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans

Kelly

Sun

Fischer

et al. 2014

Am J Respir Cell Mol Biol

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Diacetyl (DA), a component of artificial butter flavoring, has been linked to the development of bronchiolitis obliterans (BO), a disease of airway epithelial injury and airway fibrosis. The epidermal growth factor receptor ligand, amphiregulin (AREG), has been implicated in other types of epithelial injury and lung fibrosis. We investigated the effects of DA directly on the pulmonary epithelium, and we hypothesized that DA exposure would result in epithelial cell shedding of AREG. Consistent with this hypothesis, we demonstrate that DA increases AREG by the pulmonary epithelial cell line NCI-H292 and by multiple independent primary human airway epithelial donors grown under physiologically relevant conditions at the air-liquid interface. Furthermore, we demonstrate that AREG shedding occurs through a TNF-a-converting enzyme (TACE)-dependent mechanism via inhibition of TACE activity in epithelial cells using the small molecule inhibitor, TNF-a protease inhibitor-1, as well as TACE-specific small inhibitor RNA. Finally, we demonstrate supportive in vivo results showing increased AREG transcript and protein levels in the lungs of rodents with DA-induced BO. In summary, our novel in vitro and in vivo observations suggest that further study of AREG is warranted in the pathogenesis of DA-induced BO.

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Section: Discussionmentioning

confidence: 99%

Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans

Kelly

Sun

Fischer

et al. 2014

Am J Respir Cell Mol Biol

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“…In this study, we provide sound evidence that metformin can inhibit the IL-6/STAT3 axis. Also, it has been reported that TGF-b is an important inducer of pulmonary fibrosis (50), whereas metformin can significantly inhibit TGF-b signaling (15). Accordingly, the combination of metformin and EGFR-TKI may be more effective and safer for patients, because this treatment may not only overcome TKI resistance but prevent or alleviate the development of acute interstitial pneumonia.…”

Section: Metformin May Alleviate Tki-induced Interstitial Pneumoniamentioning

confidence: 99%

Metformin Sensitizes EGFR-TKI–Resistant Human Lung Cancer Cells In Vitro and In Vivo through Inhibition of IL-6 Signaling and EMT Reversal

Han

Xiao

et al. 2014

Clinical Cancer Research

222

183

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Purpose: The EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have become a standard therapy in patients with EGFR-activating mutations. Unfortunately, acquired resistance eventually limits the clinical effects and application of EGFR-TKIs. Studies have shown that suppression of epithelial-mesenchymal transition (EMT) and the interleukin (IL)-6/STAT3 pathway may abrogate this acquired mechanism of drug resistance of TKIs. This study aims to investigate the effect of metformin on sensitizing EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal.Experimental Design: The effect of metformin on reversing TKI resistance was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, invasion assay, flow cytometry analysis, immunostaining, Western blot analysis, and xenograft implantation.Results: In this study, metformin, a widely used antidiabetic agent, effectively increased the sensitivity of TKI-resistant lung cancer cells to erlotinib or gefitinib. Metformin reversed EMT and decreased IL-6 signaling activation in TKI-resistant cells, while adding IL-6 to those cells bypassed the anti-TKI-resistance effect of metformin. Furthermore, overexpression or addition of IL-6 to TKI-sensitive cells induced TKI resistance, which could be overcome by metformin. Finally, metformin-based combinatorial therapy effectively blocked tumor growth in xenografts with TKI-resistant cancer cells, which was associated with decreased IL-6 secretion and expression, EMT reversal, and decreased IL-6-signaling activation in vivo.Conclusion: Metformin, generally considered nontoxic and remarkably inexpensive, might be used in combination with TKIs in patients with non-small cell lung cancer, harboring EGFR mutations to overcome TKI resistance and prolong survival.

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“…The primer sequences for extracellular matrix genes were obtained from PrimerBank (pga.mgh.harvard. edu/primerbank/) or were the same as previously used (20,68,69).…”

Section: Il-13rα2 Membrane Expression Is Decreased In Hps Lung Tissuesmentioning

confidence: 99%

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

Zhou¹,

He²,

Herzog³

et al. 2015

J. Clin. Invest.

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Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

Cited by 127 publications

References 47 publications

Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans

Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans

Metformin Sensitizes EGFR-TKI–Resistant Human Lung Cancer Cells In Vitro and In Vivo through Inhibition of IL-6 Signaling and EMT Reversal

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

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