NFAT1 directly regulates IL-8 and MMP-3 to promote melanoma tumor growth and metastasis
Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates interleukin-2 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 p...
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Published in | Cancer research (Chicago, Ill.) Vol. 76; no. 11; pp. 3145 - 3155 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
24.03.2016
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Online Access | Get full text |
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Abstract | Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates interleukin-2 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, IL-8 and MMP-3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL-8 and MMP-3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL-8 and MMP-3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP-3 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. |
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AbstractList | Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates interleukin-2 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, IL-8 and MMP-3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL-8 and MMP-3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL-8 and MMP-3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP-3 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. |
Author | Prieto, Victor Velazquez-Torres, Guermarie Huang, Li E.Vasquez, Mayra Chakravarti, Nitin Braeuer, Russell R. Kamiya, Takafumi Shoshan, Einav Mobley, Aaron K. Villares, Gabriel J. Ivan, Cristina Bar-Eli, Menashe |
AuthorAffiliation | 4 Department of Biology, University of St. Thomas, Houston, Texas 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 3 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 1 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas |
AuthorAffiliation_xml | – name: 4 Department of Biology, University of St. Thomas, Houston, Texas – name: 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 1 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 3 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas |
Author_xml | – sequence: 1 givenname: Einav surname: Shoshan fullname: Shoshan, Einav organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 2 givenname: Russell R. surname: Braeuer fullname: Braeuer, Russell R. organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 3 givenname: Takafumi surname: Kamiya fullname: Kamiya, Takafumi organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 4 givenname: Aaron K. surname: Mobley fullname: Mobley, Aaron K. organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 5 givenname: Li surname: Huang fullname: Huang, Li organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 6 givenname: Mayra surname: E.Vasquez fullname: E.Vasquez, Mayra organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 7 givenname: Guermarie surname: Velazquez-Torres fullname: Velazquez-Torres, Guermarie organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 8 givenname: Nitin surname: Chakravarti fullname: Chakravarti, Nitin organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 9 givenname: Cristina surname: Ivan fullname: Ivan, Cristina organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 10 givenname: Victor surname: Prieto fullname: Prieto, Victor organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 11 givenname: Gabriel J. surname: Villares fullname: Villares, Gabriel J. organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas – sequence: 12 givenname: Menashe surname: Bar-Eli fullname: Bar-Eli, Menashe organization: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biology, University of St. Thomas, Houston, Texas |
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Title | NFAT1 directly regulates IL-8 and MMP-3 to promote melanoma tumor growth and metastasis |
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