Abstract
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 alpha 7 beta 1 and alpha v beta 5 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.
Highlights
Melanoma local invasion of the derma and metastatic spread by invasion of blood vessels and lymphatics are associated with alterations in cell adhesion [1, 2]
Analysis of a cDNA library obtained by subtractive hybridization from the global transcripts of a primary and a metastatic melanoma cell line derived from the same patient indicated up-regulation of CCN3 cDNA in the metastatic cells
Our study shows that CCN3 expression in melanoma affects tumor cell adhesion and dissemination
Summary
Melanoma local invasion of the derma and metastatic spread by invasion of blood vessels and lymphatics are associated with alterations in cell adhesion [1, 2]. Integrins play a major role in cell. Doi:10.1158/0008-5472.CAN-07-2103 adhesion and migration by integrating components of the extracellular matrix (ECM) to the cellular cytoskeleton and by coupling to intracellular signaling pathways that control major cellular processes, such as cell proliferation and survival [3]. Integrins regulate melanoma cell movement in response to binding to the ECM in the tumor stroma, connective tissue, or plasma membrane receptors expressed on endothelial cells [4]. The insoluble ECM, composed of proteins, glycoproteins, proteoglycans, and glycosaminoglycans in complex arrangements, provides structure and biological signals, stores soluble factors, and exerts a mechanical influence on surrounding cells, with a composition that changes in time and space with tissue-type specificity. A wide variety of integrin ligands has been detected [5], as well as different mechanisms that regulate integrin receptor functions from within the cell [6]
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