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Wnt5a and PKC, a deadly partnership involved in melanoma invasion

2007; Wiley; Volume: 20; Issue: 4 Linguagem: Inglês

10.1111/j.1600-0749.2007.00383.x

1600-0749

Estela E. Medrano,

Epigenetics and DNA Methylation

The Wnt signaling pathway controls cell fate determination in neural crest cells, which give rise to melanocytes (Dorsky et al., 1998). Activation of Wnt signaling inhibits β-catenin degradation, resulting in its nuclear accumulation. In the nucleus, β-catenin can have dual functions; it can activate transcription of LEF/TCF target genes when bound to p300 HAT, or represses transcription when tethered to HDAC1 (Billin et al., 2000). Nuclear localization of β-catenin is found in ∼30% of human melanoma specimens (Larue and Delmas, 2006). Targets of β-catenin in melanocytes and melanoma cells include the transcription factors MITF and Brn2, and the pigment gene dopachrome tautomerase (dct) (Larue and Delmas, 2006). In recent years, it has become clear that Wnt signaling can also function via β-catenin-independent pathways. These non-canonical pathways include: 1) calcium/calmodulin-dependent kinase II (CAMKII), and protein kinase C (PKC), 2) phospholipase C (PLC) and phosphodiesterase (PDE), and 3) a pathway similar to the planar polarity in Drosophila that activates the Jun-N-terminal kinase (Kikuchi et al., 2007). There are at least 19 Wnts and 10 Frizzled receptors. Wnt5a belongs to the so-called intermediate or non-transforming Wnt proteins of mouse mammary epithelial cells that also include Wnt5b, Wnt2, Wnt4, Wnt6, Wn7b and Wnt11 (Kikuchi et al., 2007). An early gene expression profiling study found Wnt5a/PKC to be associated with aggressive melanoma behavior (Bittner et al., 2000). Using Wnt5a overexpression in melanoma cell lines and a small sample of paraffin-embedded nevi, primary invasive and metastatic melanoma specimens, a follow up study demonstrated that Wnt5a activates PKC and stimulates motility and invasion of metastatic melanoma (Weeraratna et al., 2002). Supporting these results, Wnt5a expression also correlates with aggressive gastric cancer by facilitating cell migration and invasion (Kurayoshi et al., 2006). In a new study, the Weeraratna group used overexpression and down-regulation of Wnt5a, and microarray analysis to demonstrate that Wnt5a/PKC stimulates melanoma cell motility via induction of genes involved in the epithelial to mesenchymal transition (EMT) of carcinomas including up-regulation of vimentin and Snail (a repressor of E-cadherin), and down-regulation of E-cadherin (Dissanayake et al., 2007). PKC consists of ten isoforms with variable regulatory regions and conserved catalytic domains. Several isoforms play complex and sometimes opposite roles in melanogenesis, proliferation and transformation of human melanocytes. Numerous studies have consistently shown that phorbol esters have dual functions as growth promoters of normal melanocyte proliferation and as growth inhibitors of melanoma cells via the activation of different sets of PKC isoforms (Oka and Kikkawa, 2005). Using UACC1273 melanoma cells and derivatives, Dissanayake et al. demonstrated that phorbol esters increase PKC activity, expression of Snail and cell migration, whereas the PKC inhibitor Go6983 had the opposite effect. Thus both, Wnt5a and PKC appear to be critical for the invasion properties of melanoma cells. Malignant melanoma is a paradigm of the complexity and heterogeneity of human tumors. Thus, it is not surprising that other studies contradict some results by Dissanayake et al. For example, two papers demonstrated that Wnt5a and its receptor Frizzled are highly expressed in benign nevi but significantly reduced in melanomas (Pham et al., 2003; Bachmann et al., 2005). Also, a recent high–throughput study that compared gene expression profiles of cutaneous malignant melanomas (CMM) in the vertical growth phase that progressed into metastatic disease with vertical growth phase CMM without evidence of metastasis (after a median follow-up of 116 months) did not identify Wnt5a among the 243 differentially expressed genes (Alonso et al., 2007). These authors also found strong evidence of EMT signatures; 40 such genes were differentially expressed including N-cadherin, SPARC (also a repressor of E-cadherin) and osteopontin but not Snail. Technical issues and/or more complex reasons including variability in tumor thickness, ulceration and level of invasion between the tumors used in the different studies could explain the conflictive data described above. In conclusion, the studies discussed herein and previous data (Kuphal et al., 2005) support a critical role of EMT in the development of melanoma metastasis. Yet, adding to the complexity of melanoma the Sharpless group recently identified a molecularly distinct melanoma subtype that neither displays N-RAS or B-RAF mutations, nor requires EMT for progression but exhibits p53 inactivation (Shields et al., 2007).