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.
Melanoma is a devastating skin cancer characterized by distinct biological subtypes.,Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations.,Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22).,Although the vast majority (>90%) of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious.,Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found.,Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo.,Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found.,Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP).,Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs.,Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models.,Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma.