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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target. Methods Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples. Results Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG. Conclusion 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.

Original languageEnglish
Pages (from-to)960-970
Number of pages11
JournalNeuro-oncology
Volume16
Issue number7
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

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MAP Kinase Signaling System
Glioblastoma
Epidermal Growth Factor Receptor
Neoplasms
Extracellular Signal-Regulated MAP Kinases
Glioma
Phosphorylation
Cell Line
Therapeutics
Microarray Analysis
Epiregulin
Adipocytes
Carrier Proteins
Messenger RNA
Survival
Growth
Population
Genes

Keywords

  • brain tumor
  • epiregulin
  • ERK/MAPK
  • GBM

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Kohsaka, S., Hinohara, K., Wang, L., Nishimura, T., Urushido, M., Yachi, K., ... Tanaka, S. (2014). Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma. Neuro-oncology, 16(7), 960-970. https://doi.org/10.1093/neuonc/not315

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.

In: Neuro-oncology, Vol. 16, No. 7, 01.01.2014, p. 960-970.

Research output: Contribution to journalArticle

Kohsaka, S, Hinohara, K, Wang, L, Nishimura, T, Urushido, M, Yachi, K, Tsuda, M, Tanino, M, Kimura, T, Nishihara, H, Gotoh, N & Tanaka, S 2014, 'Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma', Neuro-oncology, vol. 16, no. 7, pp. 960-970. https://doi.org/10.1093/neuonc/not315
Kohsaka S, Hinohara K, Wang L, Nishimura T, Urushido M, Yachi K et al. Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma. Neuro-oncology. 2014 Jan 1;16(7):960-970. https://doi.org/10.1093/neuonc/not315
Kohsaka, Shinji ; Hinohara, Kunihiko ; Wang, Lei ; Nishimura, Tatsunori ; Urushido, Masana ; Yachi, Kazuhiro ; Tsuda, Masumi ; Tanino, Mishie ; Kimura, Taichi ; Nishihara, Hiroshi ; Gotoh, Noriko ; Tanaka, Shinya. / Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma. In: Neuro-oncology. 2014 ; Vol. 16, No. 7. pp. 960-970.
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