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Gene silencing of c-Met leads to brain metastasis inhibitory effects

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Abstract

An unfortunate consequence of improvements in the treatments of advanced primary cancers is the concurrent increase of metastatic brain tumors. Despite of unfavorable clinical prognosis, radiation therapy is still the only viable treatment option for brain metastases. Expression of c-Met induces cell migration and invasion in many cancers, which are indispensable steps for metastasis. Accordingly, we examined the effects of gene silencing of c-Met on brain metastasis to evaluate the possibility of c-Met as a potential target. MDA-MB-435 cells were transfected with c-Met targeting short hairpin RNAs (shRNAs). Effects of c-Met shRNAs on the expression of epithelial mesenchymal transition (EMT) related proteins, in vitro migration, and in vivo brain metastasis were examined. Expression of mesenchymal markers and in vitro migration of MDA-MB-435 cells were significantly inhibited by introduction of c-Met shRNAs. When c-Met-silenced MDA-MB-435 cells were stereotactically implanted into the brains of immune-compromised mice or injected into the right internal carotid arteries, c-Met-silenced MDA-MB-435 cells produced significantly smaller tumor masses or survival time was significantly prolonged, respectively, compared with MDA-MB-435 cells transfected with control shRNA. The data reveal the novel function of c-Met in the process of brain metastasis and its potential as a preventive and/or therapeutic target in this disease.

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Abbreviations

MBT:

Metastatic brain tumor

RTK:

Receptor tyrosine kinase

HGF:

Hepatocyte growth factor

SF:

Scatter factor

ICA:

Internal carotid artery

BLBC:

Basal-like breast cancer

EGFR:

Epidermal growth factor receptor

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Acknowledgments

We thank Chang In Kim, Hea Mi Kim, and Hye Rin Lee for their technical support. This work was supported by the Korea Healthcare technology R&D project, Ministry for Health & Welfare Affairs, Republic of Korea (A092255), the Samsung Medical Center grant, #GFO1130011, and the Samsung Biomedical Research Institute grant, no. SBRI C-B0-218-3 (D.H. Nam) and SBRI GL1B33011 (K.M. Joo).

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 135-710, South Korea

    Se Jeong Lee, Ho Jun Seol, Hye Won Lee, Won Young Kang, Bong Gu Kang, Juyoun Jin, Mi-Young Jo, Younggeon Jin, Jung-Il Lee & Do-Hyun Nam

  2. Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 135-710, South Korea

    Se Jeong Lee, Hye Won Lee, Won Young Kang, Bong Gu Kang, Juyoun Jin, Mi-Young Jo, Younggeon Jin & Do-Hyun Nam

  3. Cancer Stem Cell Research Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 135-710, South Korea

    Se Jeong Lee, Hye Won Lee, Won Young Kang, Bong Gu Kang, Juyoun Jin, Mi-Young Jo, Younggeon Jin, Kyeung Min Joo & Do-Hyun Nam

  4. Samsung Advanced Institute for Health Sciences and Technology (SAIHST) Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 135-710, South Korea

    Hye Won Lee, Won Young Kang, Kyeung Min Joo & Do-Hyun Nam

  5. Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, South Korea

    Se Jeong Lee & Kyeung Min Joo

  6. Center for Molecular Medicine, Samsung Biomedical Research Institute, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, South Korea

    Se Jeong Lee & Kyeung Min Joo

Authors
  1. Se Jeong Lee
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  2. Ho Jun Seol
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  3. Hye Won Lee
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  4. Won Young Kang
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  5. Bong Gu Kang
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  6. Juyoun Jin
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  7. Mi-Young Jo
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  8. Younggeon Jin
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  9. Jung-Il Lee
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  10. Kyeung Min Joo
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  11. Do-Hyun Nam
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Corresponding authors

Correspondence to Kyeung Min Joo or Do-Hyun Nam.

Additional information

Se Jeong Lee and Ho Jun Seol: contributed equally to this work.

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Lee, S.J., Seol, H.J., Lee, H.W. et al. Gene silencing of c-Met leads to brain metastasis inhibitory effects. Clin Exp Metastasis 30, 845–854 (2013). https://doi.org/10.1007/s10585-013-9584-7

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  • DOI: https://doi.org/10.1007/s10585-013-9584-7

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