title: Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression.
abstract: Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to develop more effective therapies and to identify new markers to predict disease behavior. Here, we compared the gene expression profiles of benign nevi, and non-metastatic and metastatic primary melanomas to identify any common changes in disease progression. We identified several genes associated with inflammation, angiogenesis, and extracellular matrix modification to be upregulated in metastatic melanomas. We selected one of these genes, collagen triple helix repeat containing 1 (CTHRC1), for detailed analysis, and found that CTHRC1 was expressed in both melanoma cells and the associated fibroblasts, as well as in the endothelium of tumor blood vessels. Knockdown of CTHRC1 expression by shRNAs in melanoma cells inhibited their migration in Transwell assays and their invasion in three-dimensional collagen and Matrigel matrices. We also elucidated the possible down-stream effectors of CTHRC1 by gene expression profiling of the CTHRC1-knockdown cells. Our analyses showed that CTHRC1 is regulated coordinately with fibronectin and integrin β3 by the pro-invasive and -angiogenic transcription factor NFATC2. We also found CTHRC1 to be a target of TFGβ and BRAF. These data highlight the importance of tumor stroma in melanoma progression. Furthermore, CTHRC1 was recognized as an important mediator of melanoma cell migration and invasion, providing together with its regulators-NFATC2, TGFβ, and BRAF-attractive therapeutic targets against metastatic melanomas.
authors.affiliation: Department of Pathology, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: University of Helsinki, Research Programs Unit, Translational Cancer Biology, Biomedicum Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Vadim
authors.initials: V
authors.lastname: Le Joncour
authors.affiliation: Department of Pathology, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Nummela
authors.affiliation: Department of Plastic Surgery, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Jahkola
authors.affiliation: Department of Pathology, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Virolainen
authors.affiliation: University of Helsinki, Research Programs Unit, Translational Cancer Biology, Biomedicum Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Laakkonen
authors.affiliation: Department of Dermatology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Saksela
authors.affiliation: Department of Pathology, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Erkki
authors.initials: E
authors.lastname: Hölttä
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; C502426:CTHRC1 protein, human; D016326:Extracellular Matrix Proteins; C067625:FN1 protein, human; D005353:Fibronectins; C061248:ITGB3 protein, human; D039661:Integrin beta3; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human
keywords: CTHRC1; NFATC2; TGFβ; invasion/metastasis; melanoma