Epiregulin expression by Ets-1 and ERK signaling pathway in Ki-ras-transformed cells

Cho, Min-Chul; Choi, Hee-Sook; Lee, So Jung; Kim, Bo Yeon; Jung, Mira; Park, Sue Nie; Yoon, Do‐Young

doi:10.1016/j.bbrc.2008.10.053

Cited by 23 publications

(17 citation statements)

References 23 publications

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“…21 Consistent with that result, we found that inhibition of MEK or ERK leads to a significant decrease in EREG expression in NSCLC cell lines that harbor KRAS mutations and overexpress EREG. In addition to the present findings, we have previously shown that knockdown of mutant KRAS reduced the levels of phosphorylated MEK and phosphorylated ERK.…”

Section: Discussionsupporting

confidence: 89%

“…Using a PCR-based complementary DNA (cDNA) subtraction library to isolate genes that were differentially expressed between KRAS -mutant HCT116 colon cancer cells and their KRAS -disrupted clones, Baba et al 25 identified EREG as a gene upregulated by oncogenic KRAS and demonstrated that the in vivo tumorigenicity in the KRAS -disrupted clones was partially recovered by forced expression of exogenous EREG. Elevated EREG expression was also observed in KRAS-transformed prostate epithelial cells 21 and lung tumors from mice carrying oncogenic KRAS alleles. 15,26 Collectively, these findings strongly suggest that activating KRAS mutations induce EREG overexpression, which potentially confers oncogenic KRAS-mediated lung tumorigenesis.…”

Section: Discussionmentioning

confidence: 89%

“…17,20,21 Therefore, to investigate the regulatory mechanisms of EREG expression in NSCLC cells with KRAS mutations, KRAS -mutant NSCLC cells were treated with selective inhibitors of MEK or ERK. In all cell lines, EREG expression was significantly downregulated by inhibitors of MEK (U0126) or ERK (FR180204) (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer

et al. 2012

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KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and finding druggable target molecules to inhibit oncogenic KRAS signaling is a significant challenge in NSCLC therapy. We recently identified epiregulin (EREG) as one of several putative transcriptional targets of oncogenic KRAS signaling in both KRAS-mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS. In the current study, we found that EREG is overexpressed in NSCLCs harboring KRAS, BRAF or EGFR mutations compared with NSCLCs with wild-type KRAS/BRAF/EGFR. Small interfering RNAs (siRNAs) targeting mutant KRAS, but not an siRNA targeting wild-type KRAS, significantly reduced EREG expression in KRAS-mutant and EREG-overexpressing NSCLC cell lines. In these cell lines, EREG expression was downregulated by MEK and ERK inhibitors. Importantly, EREG expression significantly correlated with KRAS expression or KRAS copy number in KRAS-mutant NSCLC cell lines. Further expression analysis using 89 NSCLC specimens showed that EREG was predominantly expressed in NSCLCs with pleural involvement, lymphatic permeation or vascular invasion and in KRAS-mutant adenocarcinomas. In addition, multivariate analysis revealed that EREG expression is an independent prognostic marker and EREG overexpression in combination with KRAS mutations was associated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS-mutant and EREG overexpressing NSCLC cells, siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis. Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 89%

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Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer

et al. 2012

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“…Epiregulin is expressed in myometrium from pregnant mice but not myometrium of pseudo pregnant mice 53. Induction of its synthesis has been linked to the RAF/MEK/ERK pathway 54.…”

Section: Commentsmentioning

confidence: 99%

Human effector/initiator gene sets that regulate myometrial contractility during term and preterm labor

Weiner

Mason

Dong

et al. 2010

American Journal of Obstetrics and Gynecology

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Objective-Distinct processes govern transition from quiescence to activation during term (TL) and preterm labor (PTL). We sought gene sets responsible for TL and PTL, along with the effector genes necessary for labor independent of gestation and underlying trigger.Methods-Expression was analyzed in term and preterm +/− labor (n =6 subjects/group). Gene sets were generated using logic operations.Results-34 genes were similarly expressed in PTL/TL but absent from nonlabor samples (Effector Set). 49 genes were specific to PTL (Preterm Initiator Set) and 174 to TL (Term Initiator Set). The gene ontogeny processes comprising Term Initiator and Effector Sets were diverse, though inflammation was represented in 4 of the top 10; inflammation dominated the Preterm Initiator Set.Comments-TL and PTL differ dramatically in initiator profiles. Though inflammation is part of the Term Initiator and the Effector Sets, it is an overwhelming part of PTL associated with intraamniotic inflammation.

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“…In the KRAS-disrupted HCT116 clones, forced expression of exogenous EREG partially recovered in vivo tumorigenicity, indicating that EREG is involved in the tumorigenesis of KRAS -mutant colon cancer. Similarly, a previous microarray analysis demonstrated that EREG expression is upregulated in KRAS-transformed human prostate cancer cell; furthermore, MEK inhibition downregulated EREG expression, accompanied by downregulation of the ETS1 transcription factor, which binds to the EREG promoter 68. EREG expression is also upregulated in lung tumors from mice carrying mutant KRAS alleles 69…”

Section: Ereg As Oncogenic Kras-regulated Genementioning

confidence: 69%

Epiregulin as a therapeutic target in non-small-cell lung cancer

Sunaga¹,

Kaira²

2015

LCTT

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Epiregulin (EREG) belongs to the ErbB family of ligands. EREG binds to EGFR and ErbB4 receptor and stimulates homodimers of EGFR and ErbB4 in addition to all possible heterodimeric ErbB complexes, resulting in the activation of downstream signaling pathways. EREG is overexpressed in various human cancers and has been implicated in tumor progression and metastasis. Oncogenic activation of the MEK/ERK pathway plays a central role in the regulation of EREG expression. Non-small-cell lung cancers (NSCLCs) harboring KRAS, BRAF, or EGFR mutations overexpress EREG, and abrogation of such mutations or inhibition of MEK or ERK downregulates the expression of EREG. Elevated EREG expression in NSCLC is associated with aggressive tumor phenotypes and unfavorable prognosis, especially in oncogenic KRAS-driven lung adenocarcinomas. The finding that attenuation of EREG inhibits cell growth and induces apoptosis in KRAS-mutant and EREG-overexpressing NSCLC cell lines suggests that targeting EREG might be a treatment option for KRAS-mutant NSCLC, although further studies are necessary to elucidate its therapeutic value. These observations suggest that oncogenic mutations in the EGFR, KRAS, or BRAF genes induce EREG upregulation through the activation of MEK/ERK pathway in NSCLC cells, whereas overproduced EREG stimulates the EGFR/ErbB receptors and activates multiple downstream signaling pathways, leading to tumor progression and metastasis of these oncogene-driven NSCLCs. This paper reviews the current understanding of the oncogenic role of EREG and highlights its potential as a therapeutic target for NSCLC.

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Epiregulin expression by Ets-1 and ERK signaling pathway in Ki-ras-transformed cells

Cited by 23 publications

References 23 publications

Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer

Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer

Human effector/initiator gene sets that regulate myometrial contractility during term and preterm labor

Epiregulin as a therapeutic target in non-small-cell lung cancer

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