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Prognostic significance of BRMS1 expression in human melanoma and its role in tumor angiogenesis

Oncogene volume 30, pages 896–906 (2011)Cite this article

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Abstract

Breast cancer metastasis suppressor 1 (BRMS1) has been reported to suppress metastasis without significantly affecting tumorigenicity in breast cancer and ovarian cancer. To investigate the role of BRMS1 in human melanoma progression and prognosis, we established tissue microarray and BRMS1 expression was evaluated by immunohistochemistry in 41 dysplastic nevi, 90 primary melanomas and 47 melanoma metastases. We found that BRMS1 expression was significantly decreased in metastatic melanoma compared with primary melanoma or dysplastic nevi (P=0.021 and 0.001, respectively, χ2 test). In addition, reduced BRMS1 staining was significantly correlated with American Joint Committee on Cancer stages (P=0.011, χ2 test), but not associated with tumor thickness, tumor ulceration and other clinicopathological parameters. Furthermore, BRMS1 expression was significantly correlated with disease-specific 5-year survival of melanoma patients (P=0.007, log-rank test). Multivariate Cox regression analysis revealed that BRMS1 staining was an independent prognostic factor for melanoma patients (relative risk=0.51; confidence interval=0.29–0.91; P=0.022). Moreover, we demonstrated that BRMS1 overexpression inhibited endothelial cell growth and tube formation ability by suppressing NF-κB activity and IL-6 expression in vitro. We also showed that knockdown of BRMS1 increased IL-6 expression and promoted endothelial cell growth and tube formation. In addition, our data revealed that the BRMS1-mediated IL-6 expression is dependent on NF-κB. Strikingly, our in vivo studies using nude mice confirmed that BRMS1 inhibited blood vessel formation and the recruitment of CD31-positive cells in matrigel plugs. Taken together, BRMS1 expression was decreased in metastatic melanomas, which resulted in deficient suppression of angiogenesis and contributed to melanoma progression. BRMS1 may serve an important prognostic marker and therapeutic target for melanoma patients.

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Acknowledgements

We thank Steve Hendy for technical assistance with EMSA. This work was supported by the Canadian Institutes of Health Research (MOP-84559 and MOP-93810) and Canadian Dermatology Foundation to GL. JL is a recipient of Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada and University of British Columbia Graduate Fellowship. Both JL and YC are recipients of CIHR Skin Research Training Centre Trainee Award.

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Authors and Affiliations

  1. Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    J Li, Y Cheng, D Tai & G Li

  2. Department of Pathology, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    M Martinka

  3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    D R Welch

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  1. J Li
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Correspondence to G Li.

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Li, J., Cheng, Y., Tai, D. et al. Prognostic significance of BRMS1 expression in human melanoma and its role in tumor angiogenesis. Oncogene 30, 896–906 (2011). https://doi.org/10.1038/onc.2010.470

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