title: A knockdown of Maml1 that results in melanoma cell senescence promotes an innate and adaptive immune response.
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.
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China. drkang6@163.com
authors.forename: Shijun
authors.initials: S
authors.lastname: Kang
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xie
authors.forename: Jingxia
authors.initials: J
authors.lastname: Miao
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Wangjun
authors.initials: W
authors.lastname: Liao
authors.forename: Rongcheng
authors.initials: R
authors.lastname: Luo
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D014162:Transfection
chemical_list: D016207:Cytokines; C486455:Maml1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors