β2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis

Takeo Nomura, Wen Chin Huang, Haiyen E. Zhau, Daqing Wu, Zhihui Xie, Hiromitsu Mimata, Majd Zayzafoon, Andrew N. Young, Fray F. Marshall, M. Neale Weitzmann, Leland W.K. Chung

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Purpose: β2-Microglobulin (β2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of β2M has been reported in human renal cell carcinoma, we investigated the effects of β2M overexpression on cancer cell growth and analyzed its molecular signaling pathway. Experimental Design: We established clonal cell lines that overexpressed β2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the β2M-mediated downstream cell signaling pathway. Results: Our results showed that β2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that β2M mediates its action through increased phosphorylation of cyclic AMP - responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, β2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. β2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the β2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase. Conclusions: Our results showed for the first time that the β2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.

Original languageEnglish (US)
Pages (from-to)7294-7305
Number of pages12
JournalClinical Cancer Research
Volume12
Issue number24
DOIs
StatePublished - Dec 15 2006

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Cyclic AMP-Dependent Protein Kinases
Renal Cell Carcinoma
Cyclic AMP
Vascular Endothelial Growth Factor A
Carrier Proteins
Growth
Phosphatidylinositol 3-Kinase
Poly(ADP-ribose) Polymerases
Caspase 9
Antigen Presentation
Mitogen-Activated Protein Kinases
Caspase 3
Small Interfering RNA
Plastics
Cell Movement
Neoplasms
Research Design
Phosphorylation
Apoptosis
Bone and Bones

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

β2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis. / Nomura, Takeo; Huang, Wen Chin; Zhau, Haiyen E.; Wu, Daqing; Xie, Zhihui; Mimata, Hiromitsu; Zayzafoon, Majd; Young, Andrew N.; Marshall, Fray F.; Weitzmann, M. Neale; Chung, Leland W.K.

In: Clinical Cancer Research, Vol. 12, No. 24, 15.12.2006, p. 7294-7305.

Research output: Contribution to journalArticle

Nomura, Takeo ; Huang, Wen Chin ; Zhau, Haiyen E. ; Wu, Daqing ; Xie, Zhihui ; Mimata, Hiromitsu ; Zayzafoon, Majd ; Young, Andrew N. ; Marshall, Fray F. ; Weitzmann, M. Neale ; Chung, Leland W.K. / β2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 24. pp. 7294-7305.
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abstract = "Purpose: β2-Microglobulin (β2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of β2M has been reported in human renal cell carcinoma, we investigated the effects of β2M overexpression on cancer cell growth and analyzed its molecular signaling pathway. Experimental Design: We established clonal cell lines that overexpressed β2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the β2M-mediated downstream cell signaling pathway. Results: Our results showed that β2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that β2M mediates its action through increased phosphorylation of cyclic AMP - responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, β2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. β2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the β2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase. Conclusions: Our results showed for the first time that the β2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.",
author = "Takeo Nomura and Huang, {Wen Chin} and Zhau, {Haiyen E.} and Daqing Wu and Zhihui Xie and Hiromitsu Mimata and Majd Zayzafoon and Young, {Andrew N.} and Marshall, {Fray F.} and Weitzmann, {M. Neale} and Chung, {Leland W.K.}",
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T1 - β2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis

AU - Nomura, Takeo

AU - Huang, Wen Chin

AU - Zhau, Haiyen E.

AU - Wu, Daqing

AU - Xie, Zhihui

AU - Mimata, Hiromitsu

AU - Zayzafoon, Majd

AU - Young, Andrew N.

AU - Marshall, Fray F.

AU - Weitzmann, M. Neale

AU - Chung, Leland W.K.

PY - 2006/12/15

Y1 - 2006/12/15

N2 - Purpose: β2-Microglobulin (β2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of β2M has been reported in human renal cell carcinoma, we investigated the effects of β2M overexpression on cancer cell growth and analyzed its molecular signaling pathway. Experimental Design: We established clonal cell lines that overexpressed β2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the β2M-mediated downstream cell signaling pathway. Results: Our results showed that β2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that β2M mediates its action through increased phosphorylation of cyclic AMP - responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, β2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. β2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the β2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase. Conclusions: Our results showed for the first time that the β2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.

AB - Purpose: β2-Microglobulin (β2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of β2M has been reported in human renal cell carcinoma, we investigated the effects of β2M overexpression on cancer cell growth and analyzed its molecular signaling pathway. Experimental Design: We established clonal cell lines that overexpressed β2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the β2M-mediated downstream cell signaling pathway. Results: Our results showed that β2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that β2M mediates its action through increased phosphorylation of cyclic AMP - responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, β2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. β2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the β2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase. Conclusions: Our results showed for the first time that the β2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.

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U2 - 10.1158/1078-0432.CCR-06-2060

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