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CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

¹ Unit of Immunotherapy of Human Tumors and ² Unit of Pathology at Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale per lo Studio e la Cura dei Tumori; ³ Institute of Pathology, University of Milan, Milan, Italy; and ⁴ Laboratoire d' Oncologie Virale et Moleculaire, UFR de Biochimie, Université Paris 7-D. Diderot, Paris, France

Requests for reprints: Monica Rodolfo, Department of Experimental Oncology, Istituto Nazionale Tumori, via G. Venezian 1, 20133 Milan, Italy. Phone: 39-02-23903235; Fax: 39-02-23902154; E-mail: monica.rodolfo{at}istitutotumori.mi.it.

Key Words: CCN3 • NOV • melanoma • cell adhesion • integrin 7β1

CCN3/nephroblastoma overexpressed belongs to the CCN family of genes that encode secreted proteins associated with the extracellular matrix (ECM) and exert regulatory effects at the cellular level. Overexpression of CCN3 was shown in metastatic melanoma cells compared with cells of the primary tumor from the same patient. Analysis of short-term cultures from 50 primary and metastatic melanomas revealed a heterogeneous expression pattern of both the 46-kDa full-length cytoplasmic/secreted protein and the 32-kDa nuclear-truncated form. The different protein expression patterns were not associated with gene alterations or polymorphisms. Like the metastatic cells expressing high levels of the 46-kDa CCN3, cells transfected to overexpress CCN3 showed increased adhesion to ECM proteins, whereas inhibition of CCN3 expression by small interfering RNA decreased adhesion to laminin and vitronectin. CCN3 overexpression induced increased expression of laminin and vitronectin integrin receptors 7β1 and vβ5 by increasing their mRNA production. Moreover, CCN3 secreted by melanoma cells acted as an adhesion matrix protein for melanoma cells themselves. Analysis of CCN3 protein expression with respect to melanoma progression detected the protein in all visceral metastases tested and in most nodal metastases from relapsing patients but in only a few nodal metastases from nonrelapsing patients and cutaneous metastases. Consistently, xenotransplantation in immunodeficient mice showed a higher metastatic potential of melanoma cells overexpressing CCN3. Together, these data indicate a role for CCN3 in melanoma cell interaction with the ECM by regulating integrin expression, resulting in altered cell adhesion and leading melanoma progression to aggressive disease. [Cancer Res 2008;68(3):715–23]

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				Correction: CCN3 Increases Integrin Expression and Adhesion Cancer Res., March 15, 2008; 68(6): 2051 - 2051. [Full Text] [PDF]