TGF-β-induced (TGFBI) protein in melanoma: a signature of high metastatic potential.
Tumor-produced extracellular matrix (ECM) proteins can be key elements in tumor growth and metastasis. Transforming growth factor beta-inducible (TGFBI) protein is a secreted ECM component that can have dual function in cancer, acting as tumor suppressor or promoter. Although TGFBI is expressed in human melanoma cells, the exact role it might have in melanoma metastasis remains elusive. Assessing the expression and secretion of TGFBI, we show that human metastatic melanomas express and secrete significantly higher amounts of TGFBI, compared with nevus lesions and primary melanoma tumors. Intravenous injection of highly metastatic human melanoma cells expressing shRNA that targets TGFBI assigns a critical role for TGFBI in the formation of melanoma distal metastases in nude mice. In vivo assays demonstrate that TGFBI silencing does not interfere with melanoma cells' dissemination to distal sites but rather with their proliferation and outgrowth within new microenvironment. In line, TGFBI silencing increases melanoma cells motility/invasion/extravasation in vitro but interferes with their progression through the cell cycle, drastically reducing their proliferation. Furthermore, we show that TGFBI is a regulator of cyclins and cyclin-dependent kinases in melanoma. Collectively, our data describe a mechanism of melanoma metastatic outgrowth via promotion of growth/survival by the ECM protein TGFBI.
Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France.
Laura
L
Lauden
INSERM UMR 1043 and CNRS UMR 5282, University Toulouse III Paul Sabatier, Toulouse, France.
Johan
J
Siewiera
Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France.
Wahid
W
Boukouaci
Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France.
Kiran
K
Ramgolam
Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France; Pharmacology-Genetics Laboratory, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France.
Samia
S
Mourah
Dermatology Department, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 976, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France.
Celeste
C
Lebbe
Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France; Jean Dausset Laboratory, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France.
Dominique
D
Charron
Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada.
Fawzi
F
Aoudjit
INSERM UMR 1043 and CNRS UMR 5282, University Toulouse III Paul Sabatier, Toulouse, France. Electronic address: nabila.jabrane-ferrat@inserm.fr.
Nabila
N
Jabrane-Ferrat
Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 940, University Paris 7-Denis Diderot, AP-HP, Saint Louis Hospital, Paris, France. Electronic address: reem.al-daccak@inserm.fr.
Reem
R
Al-Daccak
D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D002448:Cell Adhesion; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein