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2019-03-01 - Colloque/Présentation - poster - Anglais - page(s)

Journe Fabrice , "Brevican is a proteoglycan related to MITF activity with a prognostic value in melanoma" in BACR Annual meeting , Antwerpen, Belgique, 2019

  • Codes CREF : Cancérologie (DI3349)
  • Unités de recherche UMONS : Anatomie et Biologie cellulaire (M112)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)

Abstract(s) :

(Anglais) Clinical outcome of melanoma patients with metastatic disease is not reliably predicted from histopathological analyses of primary lesions and needs to be often adjusted during cancer progression. The search for more effective prognostic factors is of importance for melanoma management. Proteoglycan expression is markedly altered during malignant transformation and tumor progression. They are expressed on the cell surface and extracellular matrix of cells and tissues, playing an important role in cell-cell and cell-matrix interactions and signaling. Using microarrays, we found that brevican, a member of the chondroitin sulfate proteoglycans, was 5.7 fold more expressed in melanoma metastases (skin and lymph node metastases, n=32) of patients with overall survival lower than 30 months (p=0.0005). Accordingly, we further evaluated its expression by qPCR in 192 metastatic samples and found that high brevican mRNA level was significantly correlated with short overall survival (HR=2.7, p<0.001, Cox regression). The 10-year survival dropped to 40% in low brevican group compared to 8% in high one. In addition, using the TCGA public microarray database as a way to compare the four members of the lectican family, we could confirm that brevican was the only one differentially expressed according to 30 months cut-off survival. The mRNA expression levels of other lecticans, including aggrecan, neurocan and versican, were not significantly different between the two groups of patients. We also checked whether brevican is a target gene of MITF and found a significant correlation between both transcripts in our cohort of tissue samples (r=0.591, p<0.001, n=191, Spearman’s rho) and in a panel of melanoma cell lines (r=0.50, p=0.007, n=28). Moreover, the stimulation of MITF expression/activity in combination with MAPKi in cells with BRAF or NRAS mutation was significantly associated with an increase of brevican mRNA/protein expression, often led to the pigmentation of the cells and significantly increased cell migration in four out of six lines (p<0.05, Mann-Whitney test, Boyden chambers), thus confirming that brevican is functionally linked to the activity of the transcription factor. In conclusion, we found that brevican is the only lectican whose expression correlates with melanoma patient survival and is significantly and functionally linked to MITF. Its role in promoting cell migration can be of particular relevance in patients under MAPKi.