Clinical relevance of Neutral Endopeptidase (NEP/CD10) in melanoma

Velazquez, Yancovitz Molly, Pavlick Anna, Berman Russell, Shapiro Richard, Bogunovic Dusan, O'Neill David, Yu Yi-Lo, Spira Joanna, Christos, Zhou Xi, Mazumdar Madhu, Nanus, Liebes Leonard, Bhardwaj Nina, Polsky David, Osman Iman

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Overexpression of Neutral Endopeptidase (NEP) has been reported in metastatic carcinomas, implicating NEP in tumor progression and suggesting a role for NEP inhibitors in its treatment. We investigated the role of NEP expression in the clinical progression of cutaneous melanoma. Methods We screened 7 melanoma cell lines for NEP protein expression. NEP-specific siRNA was transfected into the lines to examine the role of gene transcription in NEP expression. Immunohistochemistry was done for 93 specimens and correlated with clinicopathologic parameters. Thirty-seven metastatic melanoma specimens were examined for NEP transcript expression using Affymetrix GeneChips. In a subset of 25 specimens for which both transcript and protein expression was available, expression ratios were used to identify genes that co-express with NEP in GeneChip analysis. Results NEP was overexpressed in 4/7 human melanoma cell lines, and siRNA knock-down of NEP transcripts led to downregulation of its protein expression. NEP protein overexpression was significantly more common in metastatic versus primary tumors (P = 0.002). Twelve of 37 (32%) metastatic tumors had increased NEP transcript expression, and an association was observed between NEP transcript upregulation and protein overexpression (P < 0.0001). Thirty-eight genes were found to significantly co-express with NEP (p < 0.005). Thirty-three genes positively correlated with NEP, including genes involved in the MAP kinase pathway, antigen processing and presentation, apoptosis, and WNT signaling pathway, and 5 genes negatively correlated with NEP, including genes of focal adhesion and the notch signaling pathways. Conclusion NEP overexpression, which seems to be largely driven by increased transcription, is rare in primary melanoma and occurs late in melanoma progression. Functional studies are needed to better understand the mechanisms of NEP regulation in melanoma.

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• Publié par: biomed
• Publié le: 01 janvier 2007
• Nombre de lectures: 26

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Journal of Translational Medicine

BioMedCentral

Open Access Research Clinical relevance of Neutral Endopeptidase (NEP/CD10) in melanoma †1,6 †1 1,2 3 Elsa F Velazquez , Molly Yancovitz , Anna Pavlick , Russell Berman , 3 2 2 2 Richard Shapiro , Dusan Bogunovic , David O'Neill , YiLo Yu , 1 4 4 4 Joanna Spira , Paul J Christos , Xi Kathy Zhou , Madhu Mazumdar , 5 2 1,2 1 David M Nanus , Leonard Liebes , Nina Bhardwaj , David Polsky and †1,2 Iman Osman*

1 2 Address: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA, Department of 3 Medicine, New York University School of Medicine, New York, NY, USA, Department of Surgery, New York University School of Medicine, New 4 5 York, NY, USA, Department of Public Health, Weill Medical College of Cornell University, New York, NY, USA, Department of Medicine, Weill 6 Medical College of Cornell University, New York, NY, USA and Department of Pathology, Brigham and Women's Hospital, Harvard School of Medicine, Boston, MA, USA

Email: Elsa F Velazquez  [e-mail]; Molly Yancovitz  [e-mail]; Anna Pavlick  [e-mail]; Russell Berman  [e-mail]; Richard Shapiro  [e-mail]; Dusan Bogunovic  [e-mail]; David O'Neill  [e-mail]; YiLo Yu  [e-mail]; Joanna Spira  [e-mail]; Paul J Christos  [e-mail]; Xi Kathy Zhou  [e-mail]; Madhu Mazumdar  [e-mail]; David M Nanus  [e-mail]; Leonard Liebes  [e-mail]; Nina Bhardwaj  [e-mail]; David Polsky  [e-mail]; Iman Osman*  [e-mail] * Corresponding author †Equal contributors

Published: 05 January 2007 Received: 11 August 2006 Accepted: 05 January 2007 Journal of Translational Medicine2007,5:2 doi:10.1186/1479-5876-5-2 This article is available from: http://www.translational-medicine.com/content/5/1/2 © 2007 Velazquez et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:Overexpression of Neutral Endopeptidase (NEP) has been reported in metastatic carcinomas, implicating NEP in tumor progression and suggesting a role for NEP inhibitors in its treatment. We investigated the role of NEP expression in the clinical progression of cutaneous melanoma. Methods:We screened 7 melanoma cell lines for NEP protein expression. NEP-specific siRNA was transfected into the lines to examine the role of gene transcription in NEP expression. Immunohistochemistry was done for 93 specimens and correlated with clinicopathologic parameters. Thirty-seven metastatic melanoma specimens were examined for NEP transcript expression using Affymetrix GeneChips. In a subset of 25 specimens for which both transcript and protein expression was available, expression ratios were used to identify genes that co-express with NEP in GeneChip analysis. Results:NEP was overexpressed in 4/7 human melanoma cell lines, and siRNA knock-down of NEP transcripts led to downregulation of its protein expression. NEP protein overexpression was significantly more common in metastatic versus primary tumors (P = 0.002). Twelve of 37 (32%) metastatic tumors had increased NEP transcript expression, and an association was observed between NEP transcript upregulation and protein overexpression (P < 0.0001). Thirty-eight genes were found to significantly co-express with NEP (p < 0.005). Thirty-three genes positively correlated with NEP, including genes involved in the MAP kinase pathway, antigen processing and presentation, apoptosis, and WNT signaling pathway, and 5 genes negatively correlated with NEP, including genes of focal adhesion and the notch signaling pathways.

Conclusion:NEP overexpression, which seems to be largely driven by increased transcription, is rare in primary melanoma and occurs late in melanoma progression. Functional studies are needed to better understand the mechanisms of NEP regulation in melanoma.

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