Downregulation of CCN3 expression as a potential mechanism for melanoma progression

Fukunaga-Kalabis, Mizuho; Martínez, Gabriela; Telson, S. M.; Liu, Z. J.; Balint, Klara; Juhász, István; Elder, David E.; Perbal, Bernard; Herlyn, Meenhard

doi:10.1038/sj.onc.1210896

Cited by 61 publications

(58 citation statements)

References 31 publications

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“…In Ewing's sarcoma, CCN3-transfected tumor cells exhibited a decreased expression of α2β1 integrin receptor, while cells lacking α2β1 are less less stably anchored to the ECM in Ewing's sarcoma tissue, resulting in increased migratory abilities (12). In melanoma, CCN3-transfected cells exhibited an increased expression of laminin and vitronectin integrin receptors α7β1 and ανβ5, resulting in increased cell adhesion (20). Integrin subunits α3, β1, αν, α2 and α5 were highly expressed by 786-O cells.…”

Section: Discussionmentioning

confidence: 99%

CCN3 (NOV) regulates proliferation, adhesion, migration and invasion in clear cell renal cell carcinoma

Liu

et al. 2012

Oncology Letters

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Abstract. The CCN3/nephroblastoma overexpressed gene belongs to the CCN family of genes that encode secreted proteins involved in a variety of processes including tumorigenesis. Altered expression of CCN3 has been observed in human nephroblastoma and renal cell carcinoma (RCC), suggesting that CCN3 plays a role in kidney tumorigenesis. The aim of the present study was to examine the role of CCN3 in clear cell RCC biology. In particular, we studied the expression of CCN3 in 32 pairs of RCC tissues and corresponding normal kidney tissues using immunohistochemistry. The CCN3 gene was transfected into the 786-O cell line and the behaviors of stably transfected clones were analyzed. Results showed the expression of CCN3 was lower in RCC tissues compared to corresponding normal kidney tissues and the expression of CCN3 was inversely correlated with the Ki67 index. CCN3-expressing clones exhibited significantly inhibited cell proliferation. Furthermore, CCN3-transfected 786-O cells exhibited increased adhesion to extracellular matrix proteins, migration and invasion in Matrigel. Our data indicated that CCN3 plays an anti-proliferative role in clear cell RCC cells and promotes the adhesion, migration and invasion of clear cell RCC cells. IntroductionRenal cell carcinoma (RCC) is the most common type of cancer of the kidney. Metastasis frequently becomes evident at the time of diagnosis or patients develop distant metastases following removal of the primary tumor. The treatment of metastatic, locally unresectable RCCs remains a challenge for urologists (1). There is a great need to understand the basic biology of RCC and develop better therapeutic options.The CCN3 (nephroblastoma overexpressed, NOV) gene belongs to the CCN family of genes, which has five additional members: cystein-rich protein 61 (Cyr61), connective tissue growth factor (CTGF), Wnt-1-induced secreted protein (WISP)-1, WISP-2 and WISP-3. CCN proteins are involved in fundamental biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, angiogenesis and tumorigenesis (2).The CCN3 protein is detectable at varying levels in the kidney, muscle, cartilage, brain, lung, ovary and heart (3-5). The functions of CCN3 protein among these different tissues are, however, different. CCN3 was originally described as antiproliferative (3), and its expression was associated with differentiation of Wilms' tumor (4), rhabdomyosarcomas (6), neuroblastomas (7), cartilaginous tumors (8), adrenocortical tumors (9) and with inhibition of the growth and decrease in tumorigenicity of several tumor cell lines including glioblastoma (10), choriocarcinoma (11) and Ewing's sarcoma (12). Furthermore, CCN3 expression was correlated with the increased proliferative index of 3T3 fibroblast (13) and tissue samples of the prostate (14). Although CCN3 reduced the growth rate of Ewing's sarcoma transfectants ex vivo, CCN3 expression was associated with poor prognosis and shown to increase cell motility, resulting in enhanced metastatic potential ...

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Section: Discussionmentioning

confidence: 99%

CCN3 (NOV) regulates proliferation, adhesion, migration and invasion in clear cell renal cell carcinoma

Liu

et al. 2012

Oncology Letters

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“…CCN3 has mostly been associated with tumour suppressor activity; inhibiting cell growth and tumourigenic potential in glioblastoma (Sin et al 2008, Fu et al 2004, melanoma (Fukunaga-Kalabis et al 2006, Fukunaga-Kalabis et al 2008) and adrenocortical tumours (Martinerie et al 2001). CCN3 has also been linked with enhanced metastatic potential for some tumours including Ewings Sarcoma ), osteosarcoma ) and prostate neoplasia (Maillard et al 2001).…”

Section: Introductionmentioning

confidence: 99%

CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in Chronic Myeloid Leukaemia

McCallum

Lü

Price

et al. 2011

J. Cell Commun. Signal.

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CCN3, a tumour suppressor gene, is downregulated as a result of BCR-ABL tyrosine kinase activity in Chronic Myeloid Leukaemia (CML). We have established a stable CCN3 expression model in the human K562 CML cell line and have further validated the role for CCN3 in the leukaemogenic process. K562 cells stably transfected with CCN3 (K562/CCN3; 2.25×10 6 copies per 50 ng cDNA) demonstrated over 50% reduction in cell growth in comparison to cells stably transfected with empty vector (K562/control; p=0.005). K562/CCN3 cells had reduced colony formation capacity (reduced by 29.7%, p=0.03) and reduced mitogenic signalling in comparison to K562/control cells (reduced by 29.5% (p=0.002) and 37.4% (p=0.017) for phosphorylation levels of ERK and AKT respectively). K562/CCN3 cells showed an accumulation of events within the subG 0 phase of the cell cycle and increased apoptosis was confirmed by a three-fold increase in annexin V binding (p<0.05). K562/CCN3 cells exposed to Imatinib (1 μM and 5 μM) showed an increase in events within the subG 0 phase of cell cycle over 96 h and mirrored the enhanced cell kill demonstrated by Annexin staining. Wild type K562 cells treated with recombinant human Ccn3 (10 nM) in combination with Imatinib (5 μM) also displayed enhanced cell kill (p=0.008). K562/CCN3 cells displayed increased adhesion to matrigel™ (2.92±0.52 fold increase compared to K562/control) which was commensurate with increased expression of the alpha 6 and beta 4 integrins (6.53±0.47 and 1.94±0.07 fold increase in gene expression respectively (n=3, p<0.05)). CCN3 restores cellular growth regulatory properties that are absent in CML and sensitises CML cells to imatinib induced apoptosis. CCN3 may provide novel avenues for the development of alternate therapeutic strategies.

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“…CCN6 is highly upregulated in osteoarthritic cartilage and is suggested to act in progressive pseudorheumatoid dysplasia through transcriptional repression of ADAMTS-5 and expression of MMP-10 (Baker et al 2012). CCN3 is not expressed in advanced melanoma cells, and its expression in aggressive Lu melanoma cells inhibits MMP-2/9 transcription and results in reduced tumor invasion (Fukunaga-Kalabis et al 2008). CCN3 enhances the migration of chondrosarcoma cells by increasing expression of MMP-13 through integrin receptors (Tzeng et al 2011).…”

Section: Discussionmentioning

confidence: 99%

The Novel Secreted Factor MIG-18 Acts with MIG-17/ADAMTS to Control Cell Migration in Caenorhabditis elegans

et al. 2014

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The migration of Caenorhabditis elegans gonadal distal tip cells (DTCs) offers an excellent model to study the migration of epithelial tubes in organogenesis. mig-18 mutants cause meandering or wandering migration of DTCs during gonad formation, which is very similar to that observed in animals with mutations in mig-17, which encodes a secreted metalloprotease of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family. MIG-18 is a novel secreted protein that is conserved only among nematode species. The mig-17(null) and mig-18 double mutants exhibited phenotypes similar to those in mig-17(null) single mutants. In addition, the mutations in fbl-1/fibulin-1 and let-2/collagen IV that suppress mig-17 mutations also suppressed the mig-18 mutation, suggesting that mig-18 and mig-17 function in a common genetic pathway. The Venus-MIG-18 fusion protein was secreted from muscle cells and localized to the gonadal basement membrane, a tissue distribution reminiscent of that observed for MIG-17. Overexpression of MIG-18 in mig-17 mutants and vice versa partially rescued the relevant DTC migration defects, suggesting that MIG-18 and MIG-17 act cooperatively rather than sequentially. We propose that MIG-18 may be a cofactor of MIG-17/ADAMTS that functions in the regulation of the gonadal basement membrane to achieve proper direction of DTC migration during gonadogenesis.T HE ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family of the secreted zinc metalloproteases has important roles in development. Nineteen ADAMTS genes have been identified in the human genome, and mutations in many result in hereditary diseases that are related to disorders of the extracellular matrix (Apte 2009). The functions of ADAMTS-5, -9, and -20 are required for digit formation, and ADAMTS-9 and -20 are needed for closure of the palate in mice (McCulloch et al. 2009;Enomoto et al. 2010). ADAMTS-5 and -15 act in myoblast fusion (Stupka et al. 2013). However, the precise roles of ADAMTS proteases in development still remain elusive.Among five ADAMTS genes in Caenorhabditis elegans, gon-1 and mig-17 play essential roles in the development of the somatic gonad (Blelloch and Kimble 1999;Nishiwaki et al. 2000). GON-1 is required for active migration of gonadal distal tip cells (DTCs), whereas MIG-17 acts in the directional control of DTC migration. Genetic suppressor analyses of mig-17 mutants identified dominant gain-of-function (gf) mutations in two genes that encode basement membrane proteins, FBL-1C/ fibulin-1C and LET-2/a2 subunit of collagen IV (Kubota et al. 2004(Kubota et al. , 2008. The suppressor fbl-1(gf) mutations result in substitutions of evolutionarily conserved amino acids within the second EGF-like motif of FBL-1C. FBL-1C is recruited to the gonadal basement membrane by MIG-17 activity, where it is likely to be required for directional control of DTC migration (Kubota et al. 2004). The suppression by fbl-1(gf) mutations depends on NID-1/nidogen, a basement membrane protein et al. ...

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Downregulation of CCN3 expression as a potential mechanism for melanoma progression

Cited by 61 publications

References 31 publications

CCN3 (NOV) regulates proliferation, adhesion, migration and invasion in clear cell renal cell carcinoma

CCN3 (NOV) regulates proliferation, adhesion, migration and invasion in clear cell renal cell carcinoma

CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in Chronic Myeloid Leukaemia

The Novel Secreted Factor MIG-18 Acts with MIG-17/ADAMTS to Control Cell Migration in Caenorhabditis elegans

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