Loss of microRNA-200a and c, and microRNA-203 expression at the invasive front of primary cutaneous melanoma is associated with increased thickness and disease progression

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• 作者：Léon C. van Kempen (121011) leon.vankempen@mcgill.ca
  Karin van den Hurk (4)
  Vladimir Lazar (5)
  Stefan Michiels (67)
  Véronique Winnepenninckx (4)
  Marguerite Stas (810)
  Alan Spatz (12310)
  Joost J. van den Oord (910)
• 关键词：E ; cadherin – Melanoma progression – Melanoma thickness – Mesenchymal characteristics – MicroRNA 200 family
• 刊名：Virchows Archiv
• 出版年：2012
• 出版时间：October 2012
• 年：2012
• 卷：461
• 期：4
• 页码：441-448
• 全文大小：322.5 KB
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• 作者单位：1. Lady Davis Institute for Medical Research, Jewish General Hospital, LDI-E447, 3755 Cote Ste-Catherine, Montreal, QC, Canada H3T 1E22. Department of Pathology, McGill University, Jewish General Hospital, Montreal, Canada3. Department of Oncology, McGill University, Jewish General Hospital, Montreal, Canada4. Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands5. Division of Functional Genomics, Gustave-Roussy Institute, Villejuif, France6. Division of Biostatistics and Epidemiology, Gustave-Roussy Institute, Villejuif, France7. Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium8. Division of Surgical Oncology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium9. Laboratory of Morphology and Molecular Pathology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium10. EORTC Melanoma Group, Brussels, Belgium11. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
• ISSN：1432-2307

文摘

Loss of E-cadherin expression in melanoma correlates with increased tumor thickness and reduced disease-free survival. The molecular mechanisms underpinning its differential expression in melanoma tissue remain elusive. MicroRNAs (miRNAs) have been implicated in tumor progression and regulation of E-cadherin expression. Here, we demonstrate a significant correlation between tumor thickness and loss of expression of miR-200a, miR-200c, and miR-203 in a series of 23 frozen primary melanomas, where it was confirmed in two subsequent validation series (series 1: six nevi, 15 primary melanomas, and 16 metastases; series 2: 11 matched pairs of primary melanomas and metastases). Decreased levels of miR-200a, miR-200c, and miR-203 correlated with increasing thickness in the combined validation series (P?=?0.024, 0.033, and 0.031, respectively). In addition, progressive loss of miR-200a expression with disease progression was observed in series 1 (P?<?0.001) and in series 2 (P?=?0.029). MiR-200 in situ hybridization and E-cadherin immunohistochemistry demonstrated reduced expression of both at the deep invasive margin of the tumor. Furthermore, a functional validation study using an anti-miR200 strategy demonstrated that loss of miR-200 expression in melanoma cell lines reduced E-cadherin expression. Collectively, our data point towards an important role for miR-200 and miR203 expression in regulating E-cadherin during melanoma progression.