Dataset Information

NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.

ABSTRACT: 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.

SUBMITTER: Shoshan E

PROVIDER: S-EPMC4891299 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.

Shoshan Einav E Braeuer Russell R RR Kamiya Takafumi T Mobley Aaron K AK Huang Li L Vasquez Mayra E ME Velazquez-Torres Guermarie G Chakravarti Nitin N Ivan Cristina C Prieto Victor V Villares Gabriel J GJ Bar-Eli Menashe M

Cancer research 20160324 11

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 i ...[more]

PMID: 27013197

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Project description:BACKGROUND:Transcription factor EGR3 (Early Growth Response 3) is a little-studied member of the EGR family that is highly expressed in human prostate tumours compared with normal tissue. Its function in prostate cancer, however, is unknown. METHODS:Stable shRNA silencing was achieved in naturally overexpressing prostate cancer cells, followed by Affymetrix expression analysis. Fold changes of ?2 and ?-2 were considered valid and t-tests P-values of ?0.01 were considered statistically significant. Potential EGR3 target genes were validated by real-time qPCR, chromatin immunoprecipitation, and gain-of-function experiments. Promoter analysis confirmed the presence of consensus binding sites in the promoters of target genes. RESULTS:Early Growth Response 3 regulates the expression of ?330 genes, 35% of which are involved in immune responses and inflammatory processes, and 15% crosstalk with the NF-?B signalling pathway. In particular, EGR3 induces the expression of over 50 secreted cytokines, growth factors, and matrix remodelling factors. Two interleukins of great relevance to prostate cancer, IL6 and IL8, were further validated as EGR3 target genes: both promoters contain EGR consensus binding sites and are pulled down in intact cells by EGR3 chromatin immunoprecipitation. Silencing of EGR3 decreased IL6 and IL8 expression, whereas overexpression of EGR3 in nontransformed cells induced IL6 and IL8 expression. CONCLUSIONS:Chronic inflammation plays a critical role in prostate cancer and elevated production of pro-inflammatory cytokines IL8 and IL6, in particular, contributes to disease progression and to the onset of castration resistance. It is shown for the first time that EGR3 is involved in the upregulation of both IL6 and IL8. Together with our previous observation that EGR3 is highly expressed in prostate tumours compared with normal tissue and strongly correlates with IL6 and IL8 expression in clinical samples, the present study suggests that EGR3 promotes excessive production of IL6 and IL8 observed during the progression of prostate cancer.

Dataset Information

NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.

Publications

NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.

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