Reciprocal regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme

Hong Zhou, Rika Miki, Mervi Eeva, Francesca M. Fike, David Seligson, Lu Yang, Akihiko Yoshimura, Michael A. Teitell, Christina A M Jamieson, Nicholas A. Cacalano

Research output: Contribution to journalArticle

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Abstract

Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay. Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.

Original languageEnglish
Pages (from-to)2344-2353
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number8
DOIs
Publication statusPublished - 2007 Apr 15
Externally publishedYes

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Glioblastoma
Ionizing Radiation
Cytokines
Cell Line
Extracellular Signal-Regulated MAP Kinases
Radiation
Mitogen-Activated Protein Kinases
Gene Expression
Methylation
Western Blotting
Polymerase Chain Reaction
Genetic Loci
Knockout Mice
Genes
Reverse Transcription
Neoplasms
Cell Survival
Research Design
Fibroblasts
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Reciprocal regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. / Zhou, Hong; Miki, Rika; Eeva, Mervi; Fike, Francesca M.; Seligson, David; Yang, Lu; Yoshimura, Akihiko; Teitell, Michael A.; Jamieson, Christina A M; Cacalano, Nicholas A.

In: Clinical Cancer Research, Vol. 13, No. 8, 15.04.2007, p. 2344-2353.

Research output: Contribution to journalArticle

Zhou, H, Miki, R, Eeva, M, Fike, FM, Seligson, D, Yang, L, Yoshimura, A, Teitell, MA, Jamieson, CAM & Cacalano, NA 2007, 'Reciprocal regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme', Clinical Cancer Research, vol. 13, no. 8, pp. 2344-2353. https://doi.org/10.1158/1078-0432.CCR-06-2303
Zhou, Hong ; Miki, Rika ; Eeva, Mervi ; Fike, Francesca M. ; Seligson, David ; Yang, Lu ; Yoshimura, Akihiko ; Teitell, Michael A. ; Jamieson, Christina A M ; Cacalano, Nicholas A. / Reciprocal regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 8. pp. 2344-2353.
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T1 - Reciprocal regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme

AU - Zhou, Hong

AU - Miki, Rika

AU - Eeva, Mervi

AU - Fike, Francesca M.

AU - Seligson, David

AU - Yang, Lu

AU - Yoshimura, Akihiko

AU - Teitell, Michael A.

AU - Jamieson, Christina A M

AU - Cacalano, Nicholas A.

PY - 2007/4/15

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N2 - Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay. Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.

AB - Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay. Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.

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