Microenvironnement inflammatoire et échappement à la réponse immunitaire anti-tumorale : le microARN-155 réprime l’expression de MITF-M dans les mélanomes

Gene MITF (Microphtalmia-associated transcription factor) generates several transcripts and proteins through the use of different promoters. The MITF-M isoform is expressed exclusively in melanocytes and is a key transcription factor that regulates, among others, many genes involved in differentiation. Indeed, MITF-M induces the expression of differentiation genes like TYR (tyrosinase), MLANA (Melan-A/Mart-1) or SILV (pMel17/gp100). In melanoma cells, the expression of these genes produce antigens that can be recognized at the surface of the tumor cells by specific CTLs (Cytolytic T Lymphocytes) able to induce the death of these cells. In the course of our study, we demonstrated that an inflammatory environment characterized by the presence of IL-1ß (Interleukin-1ß) reduced the expression of differentiation antigens consecutive to a reduction of MITF-M expression. We showed that this repression reduced the recognition of melanoma cells by CTLs directed against melanocytic differentiation antigens. We also found that this process was JNK (c-Jun N-terminal Kinase) and NF-κB (Nuclear Factor-κB) dependent. The study of the mechanisms involved in this repression of MITF-M expression induced by IL-1ß allowed us to show that the classical MITF-M promoter did not seem to be involved. However, transcriptional repression seemed to occur on a sequence of the MITF gene that differs from the classical promoter and that we were unable to identify. Following this, we found that the microRNA-155 known to be induced by NF-κB has a role in this process. Indeed, we observed that the downregulation of MITF-M was paralleled by an upregulation of miR-155 in 4 melanoma cell lines treated with IL-1ß. On the other hand, the expression of miR-155 was not induced by IL-1ß in 3 melanoma cell lines which did not show any downregulation of MITF-M. We confirmed the role of miR-155 in the IL-1ß induced repression of MITF-M by using a miR-155 specific inhibitor. Finally, in a mouse model of melanoma, we observed a strong negative correlation between the expression levels of MITF-M and tyrosinase on one hand, and miR-155 and IL-1ß on the other hand. To conclude, our results allowed us to identify a new mechanism developed by tumor cells to escape the immune response in an inflammatory environment. We demonstrated for the first time that miR-155 was able to repress the expression of MITF-M in melanoma cells. Therefore, the inhibition of miR-155 could be a new therapeutic approach to improve the classical immmunotherapy or chimiotherapy of human melanomas.