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A knockdown of Maml1 that results in melanoma cell senescence promotes an innate and adaptive immune response

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Abstract

Maml1 is emerging as a coactivator of many signaling pathways, including the Notch and Wnt pathways. Targeting Maml1 in melanoma cells efficiently knocks down the downstream transcriptional repressors Hey1 and Hes1, resulting in melanoma cell senescence, cellular differentiation, and increased melanin production. Significantly, higher IFNβ and chemokine gene transcripts have been observed, together with increased STAT1 and decreased STAT3 and NF-κB signaling activities. Although decreased cell proliferation contributes to slower tumor growth in vivo, the depletion of NK and CD8+ T cells in an shMaml1-B16 tumor carrier mouse leads to more rapid tumor growth than that observed in control shC002-B16 tumors. This result demonstrates that the knockdown of Maml1 transcription and function contributes to increased immune surveillance. The knockdown of Maml1 transcription in the human melanoma cell line M537 also results in senescence, IFNβ upregulation, increased chemokine gene expression, and greater NK and CD8+ T cell migration in a transwell system. This study demonstrated that targeting Maml1-induced tumor cell senescence and differentiation may alter the tumor microenvironment and cytokine and chemokine profiles and may also promote innate and adaptive immune cell infiltration and function.

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Abbreviations

Maml1 :

Mastermind-like protein-1

siMaml1 :

Small interfering Maml1 RNA

Hes1:

Hairy/enhancer-of-split 1

Hey1:

Hairy/enhancer-of-split related with YRPW motif 1

CCL2:

MCP-1, monocyte chemoattractant-1

CCL3:

Macrophage inflammatory protein-1α (MIP-1α)

CCL5:

Regulated upon activation normal T cell expressed and secreted (RANTES)

CCL18:

Macrophage inflammatory protein-4 (MIP-4, PARC)

CXCL9:

Monokine induced by gamma interferon (Mig)

CXCL10:

Interferon gamma-induced protein-10 (IP-10)

CXCL11:

Interferon-inducible T cell alpha chemoattractant (I-TAC, IP-9)

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Acknowledgments

This work was supported by the Province of Guangdong Science Grant (10251051501000008).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Shijun Kang, Jianmin Xie, Jingxia Miao, Rong Li, Wangjun Liao & Rongcheng Luo

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  1. Shijun Kang
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  2. Jianmin Xie
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Correspondence to Rongcheng Luo.

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Kang, S., Xie, J., Miao, J. et al. A knockdown of Maml1 that results in melanoma cell senescence promotes an innate and adaptive immune response. Cancer Immunol Immunother 62, 183–190 (2013). https://doi.org/10.1007/s00262-012-1318-1

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  • DOI: https://doi.org/10.1007/s00262-012-1318-1

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