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Melanoma dedifferentiation, characterized by the loss of MITF and MITF regulated genes and by upregulation of stemness markers as CD271, is implicated in resistance to chemotherapy, target therapy and immunotherapy. The identification of intrinsic mechanisms fostering melanoma dedifferentiation may provide actionable therapeutic targets to improve current treatments. Here, we identify NFATc2 transcription factor as an intrinsic regulator of human melanoma dedifferentiation. In panels of melanoma cell lines, NFATc2 expression correlated inversely with MITF at both mRNA and protein levels. NFATc2+/Himelanoma cell lines were CD271+and deficient for expression of melanocyte differentiation antigens (MDAs) MART-1, gp100, tyrosinase and of GPNMB, PGC1-a and Rab27a, all regulated by MITF. Targeting of NFATc2 by small interfering RNA, short hairpin RNA and by an NFATc2 inhibitor upregulated MITF, MDAs, GPNMB, PGC-1a, tyrosinase activity and pigmentation and suppressed CD271. Mechanistically, we found that NFATc2 controls melanoma dedifferentiation by inducing expression in neoplastic cells of membrane-bound tumor necrosis factor-a (mTNF-a) and that melanoma-expressed TNF-a regulates a c-myc-Brn2 axis. Specifically, NFATc2, mTNF-a and expression of TNF receptors were significantly correlated in panels of cell lines. NFATc2 silencing suppressed TNF-a expression, and neutralization of melanoma-expressed TNF-a promoted melanoma differentiation. Moreover, silencing of NFATc2 and TNF-a neutralization downmodulated c-myc and POU3F2/Brn2. Brn2 was strongly expressed in NFATc2+/HiMITFLocell lines and its silencing upregulated MITF. Targeting of c-myc, by silencing or by a c-myc inhibitor, suppressed Brn2 and upregulated MITF and MART-1 in melanoma cells. The relevance of NFATc2-dependent melanoma dedifferentiation for immune escape was shown by cytolytic T-cell assays. NFATc2HiMITFLoMDALoHLA-A2.1+melanoma cells were poorly recognized by MDA-specific and HLA-A2-restricted CTL lines, but NFATc2 targeting significantly increased CTL-mediated tumor recognition. Taken together, these results suggest that the expression of NFATc2 promotes melanoma dedifferentiation and immune escape.

The association of groups ABO with gastric cancer (1333 cases), gastric ulcer (343 cases) and duodenal ulcer (740 cases) has been studied.No correlation has been observed between gastric cancer and blood groups, whereas an heterogenic distribution of blood groups in relation to tumor site could be noted: e. g., group A was found to be associated to antral cancer, and group O to the cancer of the body and of the fundus.A highly significant heterogeneity of distribution of the groups ABO in the different ages was observed in patients bearing gastric ulcer.The correlation between duodenal ulcer and group O has been confirmed. The relative disease incidence for the subjects belonging to this group was demonstrated to be 55 per cent higher than that of group A subjects.No sex influence on groups ABO distribution was observed in the three studied conditions.

In Fig. 6e, the authors noticed that wrong blots for MITF, MART-1 expression/modulation, and for β-actin were presented, due to the similarity with experiments shown in Figure 5c. Correct MITF, MART-1, and β-actin blots were added to the revised Fig. 6 shown in the associated Correction. The meaning of the results shown in Fig.6e, as well as the conclusions of this paper were not affected, and the authors regret for this error. These errors have not been fixed in the original Article.

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