Metalloproteinase-Mediated, Context-Dependent Function of Amphiregulin and HB-EGF in Human Keratinocytes and Skin

Stoll, Stefan; Johnson, Jessica L.; Bhasin, Ajay; Johnston, Andrew; Guðjónsson, Jóhann E.; Rittié, Laure; Elder, James T.

doi:10.1038/jid.2009.211

Cited by 39 publications

(74 citation statements)

References 68 publications

(92 reference statements)

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“…In line with recent findings (Stoll et al, 2010a), our data showed that AREG is the most highly transcribed EGFR ligand in normal (control) N-TERT keratinocytes (about 70% of GAPDH expression level). TGFa message was detected at the level of about 10% of GAPDH while other EGFR ligands showed no or negligible expression in control cells (Fig.…”

Section: Depletion Of Arnt Results In Downregulation Of Amphiregulin supporting

confidence: 79%

“…In line with previous reports designating AREG as a principal EGFR ligand mediating autocrine growth in epidermal keratinocytes (Piepkorn et al, 1994;Nylander et al, 1998;Stoll et al, 2010a) we showed that AREG is the most abundant EGFR ligand in normal N-TERT cells. In N-KO keratinocytes AREG declined significantly at both mRNA and protein levels and its nuclear positivity was completely lost (Fig.…”

Section: Discussionsupporting

confidence: 77%

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ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways

Robertson¹,

Weir²,

Romanowska³

et al. 2012

Journal of Cell Science

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SummaryPreviously we showed that spatial and developmental modulation of ARNT (HIF1b) expression in mouse epidermis is essential for maintenance of keratinocyte differentiation, proper formation of the barrier and normal desquamation. Here, using lentiviral suppression or induction of ARNT in TERT-immortalized (N-TERT) and HaCaT cells we assessed the nature and mechanisms of ARNT involvement in control of differentiation in human epidermal keratinocytes. ARNT depletion did not affect the levels of basal keratins K5 and K14, but significantly induced expression of several key differentiation markers (an effect abolished by EGF supplementation). Furthermore, ARNT deficiency resulted in the downregulation of amphiregulin (AREG) -the most highly expressed EGFR ligand in human keratinocytes -whereas upregulation of ARNT showed the opposite. In ARNT-deficient monolayer cultures and 3D epidermal equivalents, the downregulation of AREG was concurrent with a decline of EGFR and ERK1/2 phosphorylation. TSA, a potent suppressor of HDAC activity, abolished the effects of ARNT deficiency, implying a role for HDACs in ARNT-dependent modulation of the AREG-EGFR pathway and downstream epidermal genes. Total HDAC activity was significantly increased in ARNT-depleted cells and decreased with ARNT overexpression. ARNT-dependent shifts in HDAC activity were specifically attributed to significant changes in the levels of HDAC1, HDAC2 and HDAC3 proteins (but not mRNA) in both monolayer and 3D cultures. Collectively, our results suggest that ARNT controls AREG expression and the downstream EGFR-ERK pathway in keratinocytes, at least in part, by modulating HDAC activity. This novel regulatory pathway targeting advanced stages of epidermal differentiation might have important implications for skin pathology such as psoriasis, atopic dermatitis and cancer.

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Section: Depletion Of Arnt Results In Downregulation Of Amphiregulin supporting

confidence: 79%

Section: Discussionsupporting

confidence: 77%

ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways

Robertson¹,

Weir²,

Romanowska³

et al. 2012

Journal of Cell Science

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“…Amphiregulin and HB-EGF show different biological activities in target cells (21), with amphiregulin mainly stimulating cell proliferation (22) and HB-EGF stimulating chemotaxis (23). Amphiregulin binds to ErbB1 (EGFR), whereas HB-EGF binds to both ErbB1 (EGFR) and ErbB4 (24).…”

Section: Hb-egf Markedly Enhances Migration and Proliferation Of Humamentioning

confidence: 99%

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

Yasumoto

Yamada

Kawashima

et al. 2011

Clinical Cancer Research

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Purpose: Peritoneal carcinomatosis, often associated with malignant ascites, is the most frequent cause of death in patients with advanced gastric cancer. We previously showed that the CXCR4/CXCL12 axis is involved in the development of peritoneal carcinomatosis from gastric cancer. Here, we investigated whether epidermal growth factor receptor (EGFR) ligands are also involved in the development of peritoneal carcinomatosis from gastric cancer.Experimental Design: The functional involvement of expression of the ErbB family of receptors and/or EGFR ligands was examined in CXCR4-expressing human gastric cancer cells and fibroblasts, clinical samples (primary tumors and ascites), and an animal model.Results: High concentration of the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor (HB-EGF), as well as of CXCL12, were present in malignant ascites. Human gastric cancer cell lines and primary gastric tumors, with high potential to generate peritoneal carcinomatosis, expressed high levels of EGFR and CXCR4 mRNA and protein. Both amphiregulin and HB-EGF enhanced the proliferation, migration, and functional CXCR4 expression in highly CXCR4-expressing gastric cancer NUGC4 cells. Amphiregulin strongly enhanced the proliferation of NUGC4 cells, whereas HB-EGF markedly induced the migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNFa-converting enzyme (TACE)-dependent amphiregulin shedding from NUGC4 cells. In an experimental peritoneal carcinomatosis model in mice, cetuximab effectively reduced tumor growth and ascites formation.Conclusions: Our results strongly suggest that the EGFR ligands amphiregulin and HB-EGF play an important role, interacting with the

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“…In this study, we focused on one target of miR-132 -HB-EGF -which is one of the EGFR ligands, in addition to TGFα, amphiregulin (AR), epiregulin (EREG), and β cellulin, that is expressed by keratinocytes in an autocrine fashion (39,40). Unlike the other EGFs, overexpression of HB-EGF in keratinocytes was previously reported to lead to a large decrease in cell Inhibition of miR-132 delays reepithelialization of human ex vivo skin wounds.…”

Section: Lack Of Mir-132 Delays Skin Wound Healing In Vivomentioning

confidence: 99%

MicroRNA-132 enhances transition from inflammation to proliferation during wound healing

Li¹,

Wang²,

Liu³

et al. 2015

J. Clin. Invest.

170

173

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Metalloproteinase-Mediated, Context-Dependent Function of Amphiregulin and HB-EGF in Human Keratinocytes and Skin

Cited by 39 publications

References 68 publications

ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways

ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

MicroRNA-132 enhances transition from inflammation to proliferation during wound healing

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