NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis
| Autor: | Li Huang, Victor G. Prieto, Menashe Bar-Eli, Einav Shoshan, Mayra E. Vasquez, Russell R. Braeuer, Takafumi Kamiya, Gabriel J. Villares, Aaron K. Mobley, Guermarie Velazquez-Torres, Cristina Ivan, Nitin Chakravarti |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms T cell Blotting Western Mice Nude Apoptosis Biology Real-Time Polymerase Chain Reaction Article Metastasis Immunoenzyme Techniques Mice 03 medical and health sciences 0302 clinical medicine Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Neoplasm Invasiveness RNA Messenger Neoplasm Metastasis Melanoma Transcription factor Cell Proliferation Neoplasm Staging Mice Inbred BALB C Tumor microenvironment NFATC Transcription Factors Reverse Transcriptase Polymerase Chain Reaction Cell growth Interleukin-8 Cancer Prognosis medicine.disease Xenograft Model Antitumor Assays Survival Rate 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Immunology Cancer research Female Matrix Metalloproteinase 3 Autotaxin |
| Zdroj: | Cancer Research. 76:3145-3155 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates IL2 expression during T-cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in cancer is not completely understood. We previously demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the autotaxin gene (Enpp2). Here, we report a strong correlation between NFAT1 expression and metastatic potential in melanoma cell lines and tumor specimens. To elucidate the mechanisms underlying NFAT1 overexpression during melanoma progression, we conducted a microarray on a highly metastatic melanoma cell line in which NFAT1 expression was stably silenced. We identified and validated two downstream targets of NFAT1, IL8, and MMP3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL8 and MMP3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL8 and MMP3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP3 promoted melanoma tumor growth and lung metastasis. Collectively, our findings assign a new role for NFAT1 in melanoma progression, underscoring the multifaceted functions that immunomodulatory factors may acquire in an unpredictable tumor microenvironment. Cancer Res; 76(11); 3145–55. ©2016 AACR. |
| Databáze: | OpenAIRE |
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