Activation of Notch1 signaling is required for β-catenin–mediated human primary melanoma progression
Klara Balint, Min Xiao, Chelsea C. Pinnix, Akinobu Soma, Imre Veres, Istvan Juhasz, Eric J. Brown, Anthony J. Capobianco, Meenhard Herlyn, Zhao-Jun Liu
Klara Balint, Min Xiao, Chelsea C. Pinnix, Akinobu Soma, Imre Veres, Istvan Juhasz, Eric J. Brown, Anthony J. Capobianco, Meenhard Herlyn, Zhao-Jun Liu
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Research Article Oncology

Activation of Notch1 signaling is required for β-catenin–mediated human primary melanoma progression

Abstract

Notch is a highly conserved transmembrane receptor that determines cell fate. Notch signaling denotes cleavage of the Notch intracellular domain, its translocation to the nucleus, and subsequent activation of target gene transcription. Involvement of Notch signaling in several cancers is well known, but its role in melanoma remains poorly characterized. Here we show that the Notch1 pathway is activated in human melanoma. Blocking Notch signaling suppressed whereas constitutive activation of the Notch1 pathway enhanced primary melanoma cell growth both in vitro and in vivo yet had little effect on metastatic melanoma cells. Activation of Notch1 signaling enabled primary melanoma cells to gain metastatic capability. Furthermore, the oncogenic effect of Notch1 on primary melanoma cells was mediated by β-catenin, which was upregulated following Notch1 activation. Inhibiting β-catenin expression reversed Notch1-enhanced tumor growth and metastasis. Our data therefore suggest a β-catenin–dependent, stage-specific role for Notch1 signaling in promoting the progression of primary melanoma.

Authors

Klara Balint, Min Xiao, Chelsea C. Pinnix, Akinobu Soma, Imre Veres, Istvan Juhasz, Eric J. Brown, Anthony J. Capobianco, Meenhard Herlyn, Zhao-Jun Liu

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Figure 1

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Expression of Notch pathway components in human melanocytes and melanoma...
Expression of Notch pathway components in human melanocytes and melanoma cells. (A) Immunohistochemistry for Notch1 in primary lesions of human malignant melanoma and in nevi. Specimens were stained using standard immunoperoxidase methods. Reddish staining indicates Notch1 positivity whereas brown staining indicates melanin. Negative control was stained with isotype-matched secondary antibodies. HMB45 staining confirmed melanocytic origin. Scale bars: 200 μm. High-magnification images are shown in the right column. Scale bar: 20 μm. (B) Western blot analysis for the levels of activated Notch1 in human melanocytes and melanoma cell lines. Increased levels of activated Notch1 in most melanoma cell lines compared with melanocytes. β-actin was used as loading control. (C) HEY1, HEY2, HES1, and HES2 mRNA expression in normal and malignant melanocytic cells as determined by quantitative real-time RT-PCR. Results are mean ± SD of 3 independent experiments. *P < 0.05, Student’s t test. (D) Relative amounts of JAGGED1 mRNA expression in normal and malignant melanocytic cells as determined by quantitative real-time RT-PCR. Results are mean ± SD of 3 independent experiments.