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Regulation of HGF-mediated cell proliferation and invasion through NF-κB, JunB, and MMP-9 cascades in stomach cancer cells

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Abstract

Blocking of activator protein-1 activity leads to suppression of growth factor-induced transformation. However, the role of individual components of the Jun family in this process is unclear. Over-expression of JunB has been reported to be associated with neoplastic transformation and regulation of Matrix metalloproteinase-9 (MMP-9) expression. Using cDNA microarray, we found that JunB might be one of target genes up-regulated by hepatocyte growth factor (HGF). Therefore, we tried to investigate the role of JunB in HGF-medicated cell proliferation and cell invasion in human gastric cancer cells, NUGC3 and MKN28. We verified that HGF increased JunB in time and dose-dependent manners. The JunB levels were decreased by the treatment with an NF-κB inhibitor, pyrrolidine dithiocarbamate. Down-regulation of JunB by transfecting cells with JunB-short hairpin RNAs (shRNA) inhibited MMP-9 up-regulation induced by HGF. Furthermore, transfection with JunB-shRNA repressed HGF-mediated increases in cell proliferation and cell invasion. These data suggest that JunB might be regulated through an NF-κB pathway and up-regulation of JunB induced by HGF might play an important role in the regulation of cell proliferation and cell invasion through MMP-9 expression. In conclusion, these results may contribute to the JunB-associated malignant phenotype of gastric cancers by regulating MMP-9, and serve as a novel therapeutic target for stomach cancer therapy in the future.

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Abbreviations

HGF:

Hepatocyte growth factor

MMP:

Matrix metalloproteinase

NF-κB:

Nuclear factor-kappa B

AP-1:

Activator protein-1

PDTC:

Pyrrolidine dithiocarbamate

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MEST) (No. 2010-0028447) (No. 2011-0006179).

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Authors and Affiliations

  1. Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Republic of Korea

    Kyung Hee Lee

  2. Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong, Daegu, 705-717, Republic of Korea

    Jae-Ryong Kim

  3. The Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea

    Jae-Ryong Kim

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  1. Kyung Hee Lee
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Correspondence to Jae-Ryong Kim.

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Lee, K.H., Kim, JR. Regulation of HGF-mediated cell proliferation and invasion through NF-κB, JunB, and MMP-9 cascades in stomach cancer cells. Clin Exp Metastasis 29, 263–272 (2012). https://doi.org/10.1007/s10585-011-9449-x

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