Deficient transforming growth factor-β1 activation and excessive insulin-like growth factor II (IGFII) expression in IGFII receptor-mutant tumors

Suna Wang, Rhonda F. Souza, Dehe Kong, Jing Yin, Kara N. Smolinski, Tong Tong Zou, Tom Frank, Joanne Young, Kathleen C. Flanders, Haruhiko Sugimura, John M. Abraham, Stephen J. Meltzer

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Abstract

The insulin-like growth factor II receptor (IGFIIR) gene has been identified as a coding region target of microsatellite instability in human gastrointestinal (GI) tumors. IGFIIR normally has two growth-suppressive functions: it binds and stimulates the plasmin-mediated cleavage and activation of the latent transforming growth factor-β1 (LTGF-β1) complex, and it mediates the internalization and degradation of IGFII ligand, a mitogen. We used an immunohistochemical approach to determine whether IGFIIR mutation affected expression of these proteins in GI tumors. Four highly specific antibodies were used: LC(1-30), which recognizes the active form of TGF-β1; anti-LTGF-β1, which detects the LTGF-β1 precursor protein; anti- IGFIIR; and anti-IGFII ligand. Twenty GI tumors either with (6 of 20) or without (14 of 20) known IGFIIR mutation were examined, along with matching normal tissues. Results were statistically significant in the following categories: (a) decreased active TGF-β1 protein expression in IGFIIR-Mutant tumor tissues versus matching normal tissues or IGFIIR-Wild-Type tumor tissues; (b) increased LTGF-β1 protein expression in IGFIIR-Mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; and (c) increased IGFII ligand protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues. These data suggest that in genetically unstable GI tumors, mutation of a micro-satellite within the coding region of IGFIIR functionally inactivates this gene, causing both diminished growth suppression (via decreased activation of TGF- β1) and augmented growth stimulation (via decreased degradation of the IGFII ligand).

Original languageEnglish (US)
Pages (from-to)2543-2546
Number of pages4
JournalCancer Research
Volume57
Issue number13
StatePublished - Jul 1 1997

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IGF Type 2 Receptor
Transforming Growth Factors
Somatomedins
Insulin-Like Growth Factor II
Neoplasms
Ligands
Mutation
Proteins
Growth
Somatomedin Receptors
Microsatellite Instability
Protein Precursors
Fibrinolysin
Mitogens
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Deficient transforming growth factor-β1 activation and excessive insulin-like growth factor II (IGFII) expression in IGFII receptor-mutant tumors. / Wang, Suna; Souza, Rhonda F.; Kong, Dehe; Yin, Jing; Smolinski, Kara N.; Zou, Tong Tong; Frank, Tom; Young, Joanne; Flanders, Kathleen C.; Sugimura, Haruhiko; Abraham, John M.; Meltzer, Stephen J.

In: Cancer Research, Vol. 57, No. 13, 01.07.1997, p. 2543-2546.

Research output: Contribution to journalArticle

Wang, S, Souza, RF, Kong, D, Yin, J, Smolinski, KN, Zou, TT, Frank, T, Young, J, Flanders, KC, Sugimura, H, Abraham, JM & Meltzer, SJ 1997, 'Deficient transforming growth factor-β1 activation and excessive insulin-like growth factor II (IGFII) expression in IGFII receptor-mutant tumors', Cancer Research, vol. 57, no. 13, pp. 2543-2546.
Wang, Suna ; Souza, Rhonda F. ; Kong, Dehe ; Yin, Jing ; Smolinski, Kara N. ; Zou, Tong Tong ; Frank, Tom ; Young, Joanne ; Flanders, Kathleen C. ; Sugimura, Haruhiko ; Abraham, John M. ; Meltzer, Stephen J. / Deficient transforming growth factor-β1 activation and excessive insulin-like growth factor II (IGFII) expression in IGFII receptor-mutant tumors. In: Cancer Research. 1997 ; Vol. 57, No. 13. pp. 2543-2546.
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abstract = "The insulin-like growth factor II receptor (IGFIIR) gene has been identified as a coding region target of microsatellite instability in human gastrointestinal (GI) tumors. IGFIIR normally has two growth-suppressive functions: it binds and stimulates the plasmin-mediated cleavage and activation of the latent transforming growth factor-β1 (LTGF-β1) complex, and it mediates the internalization and degradation of IGFII ligand, a mitogen. We used an immunohistochemical approach to determine whether IGFIIR mutation affected expression of these proteins in GI tumors. Four highly specific antibodies were used: LC(1-30), which recognizes the active form of TGF-β1; anti-LTGF-β1, which detects the LTGF-β1 precursor protein; anti- IGFIIR; and anti-IGFII ligand. Twenty GI tumors either with (6 of 20) or without (14 of 20) known IGFIIR mutation were examined, along with matching normal tissues. Results were statistically significant in the following categories: (a) decreased active TGF-β1 protein expression in IGFIIR-Mutant tumor tissues versus matching normal tissues or IGFIIR-Wild-Type tumor tissues; (b) increased LTGF-β1 protein expression in IGFIIR-Mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; and (c) increased IGFII ligand protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues. These data suggest that in genetically unstable GI tumors, mutation of a micro-satellite within the coding region of IGFIIR functionally inactivates this gene, causing both diminished growth suppression (via decreased activation of TGF- β1) and augmented growth stimulation (via decreased degradation of the IGFII ligand).",
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AU - Yin, Jing

AU - Smolinski, Kara N.

AU - Zou, Tong Tong

AU - Frank, Tom

AU - Young, Joanne

AU - Flanders, Kathleen C.

AU - Sugimura, Haruhiko

AU - Abraham, John M.

AU - Meltzer, Stephen J.

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