Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion.

Tiphaine Delaunay,Maria Brattsand,Francine Walker,Antoninus Soosaipillai,Dalila Darmoul,Meriem Haddada,Feryel Soualmia,Viktor Magdolen,Eleftherios P Diamandis,Chahrazade El Amri,Lydia Deschamps

doi:10.1002/1878-0261.12103

Abstract

Members of the tissue kallikrein‐related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed. Herein, we demonstrate that although mRNA of several KLKs are aberrantly expressed in melanoma cell lines, only the KLK7 protein is highly secreted in vitro. In line with these findings, ectopic expression of KLK7 in human melanomas and its absence in benign nevi were demonstrated by immunohistochemistry in vivo. Interestingly, overexpression of KLK7 induced a significant reduction in melanoma cell proliferation and colony formation. Moreover, KLK7 overexpression triggered an increase in cell motility and invasion associated with decreased expression of E‐cadherin and an upregulation of MCAM/CD146. Our results demonstrate, for the first time, that aberrant KLK7 expression leads to a switch from proliferative to invasive phenotype, suggesting a potential role of KLK7 in melanoma progression. Thus, we hypothesize that KLK7 may represent a potential biomarker for melanoma progression.

Highlights

Despite recent advances in the understanding of oncogenic mechanisms and therapeutic intervention, melanoma is the most aggressive skin cancer with poor prognosis in the metastatic stage
As recent studies point to the importance of kallikrein-related peptidase (KLK) in melanoma progression (Martins et al, 2011; Rezze et al, 2011), we aimed at investigating the expression pattern of KLKs in melanoma cells. mRNA levels of several KLKs were analyzed by RT-polymerase chain reaction (PCR) in 23 human melanoma cell lines
One of our main findings is that several KLKs are ectopically expressed in skin melanomas compared to normal melanocytes, which do not express any of the KLK genes analyzed

Summary

Introduction

Despite recent advances in the understanding of oncogenic mechanisms and therapeutic intervention, melanoma is the most aggressive skin cancer with poor prognosis in the metastatic stage. Clinical and histopathological evidence suggests that melanoma develops sequentially, progressing from primary in situ melanomas, to invasive primary lesions, and to metastases (Haass and Herlyn, 2005). The outlined steps involve molecular changes that include acquisition of the epithelial–mesenchymal-like transition (EMT-like) associated with changes in cell surface adhesion molecules and activation of signaling pathways leading to cell dissemination (Haass and Herlyn, 2005). Despite extensive efforts concerning characterization of malignant melanoma, no specific molecular markers are currently available that are clearly related to the progression of this disease. A growing body of evidence has identified diverse mechanisms by which proteases affect cancer progression and metastasis through complex processes that involve cleavage of cell adhesion molecules, growth factors, and cytokines (Sevenich and Joyce, 2014). Besides some other serine proteases, certain members of the kallikrein-related peptidase (KLK) family serve as signaling molecules controlling cell functions through specific membrane receptors, the protease-activated receptors (PARs) (Darmoul et al, 2001, 2003, 2004; Gratio et al, 2010, 2011; Ramsay et al, 2008)

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Results

Conclusion