SOCS1 favors the epithelial-mesenchymal transition in melanoma, promotes tumor progression and prevents antitumor immunity by PD-L1 expression

• Published in: Scientific reports 2017-01, Vol.7 (1), p.40585-40585, Article 40585
• Main Authors: Berzaghi, R., Maia, V. S. C., Pereira, F. V., Melo, F. M., Guedes, M. S., Origassa, C. S. T., Scutti, J. B., Matsuo, A. L., Câmara, N. O. S., Rodrigues, E. G., Travassos, L. R.
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/31; 13/89; 14; 45; 45/61; 631/67/1813/1634; 631/67/327; 64; 64/60; 82/51; Animals; B7-H1 Antigen - metabolism; Bone Morphogenetic Protein Receptors, Type I - metabolism; Bone Morphogenetic Proteins - metabolism; c-Kit protein; Cadmium; CD8-Positive T-Lymphocytes - immunology; Cell adhesion & migration; Cell cycle; Cell migration; Cell size; Cyclic AMP Response Element-Binding Protein - metabolism; Disease Progression; DNA microarrays; Down-regulation; Epidermal growth factor; Epithelial-Mesenchymal Transition - genetics; Extracellular signal-regulated kinase; Fibroblast growth factor receptors; Gene Expression Regulation, Neoplastic; Gene Silencing; Growth factor receptors; Growth factors; Humanities and Social Sciences; Immune response; Immunity; Immunization; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma-Specific Antigens - metabolism; Mesenchyme; Mice, Inbred C57BL; multidisciplinary; NF-kappa B - metabolism; Nuclei; PD-L1 protein; Phosphorylation; Protective Agents - metabolism; Protein-tyrosine kinase; Receptor Protein-Tyrosine Kinases - metabolism; Reversion; S phase; Science; Signal Transduction; Smad Proteins - metabolism; Stat3 protein; Suppressor of Cytokine Signaling 1 Protein - metabolism; Transcription Factor AP-2 - metabolism; Transcription, Genetic; Transforming Growth Factor beta - metabolism; Tumor cells; Tumor Microenvironment; Tumors; Up-Regulation - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep40585

Silencing of SOCS1 protein with shRNAi lentivirus (shR-SOCS1) led to partial reversion of the tumorigenic phenotype of B16F10-Nex2 melanoma cells. SOCS1 silencing inhibited cell migration and invasion as well as in vitro growth by cell cycle arrest at S phase with increased cell size and nuclei. Down-regulation of SOCS1 decreased the expression of epidermal growth factor receptor, Ins-Rα, and fibroblast growth factor receptors. The present work aimed at analyzing the SOCS1 cell signaling and expression of proteins relevant to tumor development. An RNA microarray analysis of B16F10-Nex2 melanoma cells with SOCS1 silenced by shRNAi-SOCS1 was undertaken in comparison with cells transduced with the empty vector. Among 609 differentially expressed genes, c-Kit, Met and EphA3 cytokine/tyrosine-kinase (TK) receptors were down regulated. A significant decrease in the expression of TK receptors, the phosphorylation of mediators of ERK1/2 and p38 pathways and STAT3 (S727) were observed. Subcutaneous immunization with shR-SOCS1-transduced viable tumor cells rendered protection against melanoma in a syngeneic model, with decreased expression of PD-L1 and of matrix metallo-proteinases (MMPs) and CD-10 in those cells. The present work shows the role of SOCS1 in murine melanoma development and the potential of SOCS1-silenced tumor cells in raising an effective anti-melanoma immune response.