Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma

Kohsaka, Shinji; Hinohara, Kunihiko; Wang, Lei; Nishimura, Tatsunori; Urushido, Masana; Yachi, Kazuhiro; Tsuda, Masumi; Tanino, Mishie; Kimura, Taichi; Nishihara, Hiroshi; Gotoh, Noriko; Tanaka, Shinya

doi:10.1093/neuonc/not315

Cited by 42 publications

(42 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These two sites have been shown to be phosphorylated and activated by EGFR ligands. 37, 38, 39 Using RRPA, we observed significantly higher levels of EGFR phosphorylation in carcinomas and metastases compared with adenomas at both sites (Figure 3d), consistent with EGFR signaling being activated at the adenoma–carcinoma transition and maintained in distant CRC metastases. Moreover, a significant inverse correlation between EREG promoter methylation and EGFR phosphorylation was also observed at both sites in adenomas, carcinomas and metastases (Figure 3e).…”

Section: Resultssupporting

confidence: 60%

“…Studies have suggested that the ERK/MAPK pathway is activated and might help drive tumorigenesis downstream of EREG-driven EGFR phosphorylation in hepatocytes and in glioblastomas. 37, 38 Although we observed higher levels of ERK/MAPK signaling in CRC compared with adenomas in our sample set, future studies will be required to assess the signaling downstream of EGFR-Y1068 and -Y1173 in CRC in more detail.…”

Section: Discussionmentioning

confidence: 72%

“…We next assessed the basal EGFR phosphorylation levels in these 10 cell lines at the EGFR-Y1068 and -Y1173 sites that are known to be indicative of receptor activation. 37, 38, 39 We found cell lines with high basal levels of EREG methylation and low basal levels of expression (Colo302DM, Colo741 and RKO) to have barely detectable levels of EGFR phosphorylation at both sites (Figure 5c). In contrast, EREG phosphorylation was readily detectable in cell lines with intermediate levels of EREG expression and methylation (C2BBe1, CL11 and HCA7) and in cell lines with low basal levels of EREG methylation and intermediate/high EREG expression levels (HCT15, SW48, HCT116 and in DLD-1) (Figures 5a–c).…”

Section: Resultsmentioning

confidence: 87%

See 2 more Smart Citations

Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter

Qu¹,

Sandmann²,

Frierson

et al. 2016

Oncogene

View full text Add to dashboard Cite

Key molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) are well described. However, the mechanisms through which clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we used an integrative genomics approach to examine CRC progression. We used laser capture microdissection to isolate colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas and metastases, and used gene expression profiling to identify pathways that were differentially expressed between the different cell types. We identified a number of potentially important transcriptional changes in developmental and oncogenic pathways, and noted a marked upregulation of EREG in primary and metastatic cancer cells. We confirmed this pattern of gene expression by in situ hybridization and observed staining consistent with autocrine expression in the tumor cells. Upregulation of EREG during the adenoma–carcinoma transition was associated with demethylation of two key sites within its promoter, and this was accompanied by an increase in the levels of epidermal growth factor receptor (EGFR) phosphorylation, as assessed by reverse-phase protein analysis. In CRC cell lines, we demonstrated that EREG demethylation led to its transcriptional upregulation, higher levels of EGFR phosphorylation, and sensitization to EGFR inhibitors. Low levels of EREG methylation in patients who received cetuximab as part of a phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers, including those of the head and neck, lung and bladder. Therefore, we propose that upregulation of EREG expression through promoter demethylation might be an important means of activating the EGFR pathway during the genesis of CRC and potentially other cancers.

show abstract

Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 87%

See 1 more Smart Citation

Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter

Qu¹,

Sandmann²,

Frierson

et al. 2016

Oncogene

View full text Add to dashboard Cite

show abstract

“…Other pathways, however, may activate this kinase, including protein kinase C (PKC) [60,97] and even CD133 -the latter by unknown mechanisms [98] . This interaction with CD133 may feature MAPK as a protein associated with stemness, although more studies are required to fully understand MAPK's importance in this cell population [99] . It has also been reported that MAPK interacts with the PI3K pathway; this interaction affects the nuclear localization of MAPK [100] probably through the regulation of mTOR-inducing transcription and cell cycle progression [101] .…”

Section: Mitogen-activated Protein Kinases (Mapks)mentioning

confidence: 99%

Growth factors and kinases in glioblastoma growth

Peña-Ortiz¹,

Germán-Castelán²,

González-Arenas³

2016

Adv Mod Oncol Res

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer, having the highest invasion, migration, proliferation, and angiogenesis rates. Several signaling pathways are involved in the regulation of these processes including growth factors and their tyrosine kinase receptors, such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFβ), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). Different kinases and regulators also participate in signaling pathways initiated by growth factors, such as mitogen-activated kinases (MAPK), protein kinases C (PKC), phosphatidylinositol-3 kinases (PI3K), protein kinase B (PKB or Akt), glycogen synthase kinase 3β (GSK3β), the mTOR complex, and Bcl-2. In this review, we will focus on the role of these proteins as possible therapeutic targets in GBM.

show abstract

“…EREG is overexpressed in many human cancers, such as pancreatic cancer, colon cancer, NSCLC, breast cancer, bladder cancer, prostate cancer, kidney cancer, liver cancer, ovarian cancer, oral cancer, thymic cancer, salivary adenoid cystic carcinoma, and malignant glioma, whereas EREG expression levels in normal adult tissues are extremely low 30,38–54. For instance, thymic carcinomas had a high percentage (91.7%) of immunohistochemical expression of EREG 50…”

Section: Role Of Ereg In Cancermentioning

confidence: 99%

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

Sunaga¹,

Kaira²

2015

LCTT

View full text Add to dashboard Cite

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.

show abstract

Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma

Abstract: These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients.

Cited by 42 publications

References 46 publications

Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter

Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter

Growth factors and kinases in glioblastoma growth

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

Contact Info

Product

Resources

About