Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway
The treatment of melanoma has remained a difficult challenge. Targeting the tumor stroma has recently attracted attention for developing novel strategies for melanoma therapy. Activating transcription factor 3 (ATF3) plays a crucial role in regulating tumorigenesis and development, but whether the e...
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doaj-7a91b580bf4e4703b99dc194358b579d2020-11-25T03:10:24ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-04-011010.3389/fonc.2020.00624536966Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine PathwayTingjian Zu0Tingjian Zu1Jie Wen2Jie Wen3Lin Xu4Lin Xu5Lin Xu6Hui Li7Jun Mi8Jun Mi9Hui Li10Cord Brakebusch11David E. Fisher12Xunwei Wu13Xunwei Wu14Xunwei Wu15Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, ChinaShandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, ChinaDepartment of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, ChinaShandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, ChinaDepartment of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, ChinaShandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, ChinaDepartment of Orthodontics, Liaocheng People's Hospital, Liaocheng, ChinaDepartment of Dermatology, Qilu Hospital of Shandong University, Jinan, ChinaDepartment of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, ChinaShandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, ChinaDepartment of Hematology, Southwest Hospital, Third Military Medical University, Chongqing, ChinaBiotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, DenmarkCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, ChinaShandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, ChinaCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesThe treatment of melanoma has remained a difficult challenge. Targeting the tumor stroma has recently attracted attention for developing novel strategies for melanoma therapy. Activating transcription factor 3 (ATF3) plays a crucial role in regulating tumorigenesis and development, but whether the expression of ATF3 in human dermal fibroblasts (HDFs) can affect melanoma development hasn't been studied. Our results show that ATF3 expression is downregulated in stromal cells of human melanoma. HDFs expressing high levels of ATF3 suppressed the growth and migration of melanoma cells in association with downregulation of different cytokines including IL-6 in vitro. In vivo, HDFs with high ATF3 expression reduced tumor formation. Adding recombinant IL-6 to melanoma cells reversed those in vitro and in vivo effects, suggesting that ATF3 expression by HDFs regulates melanoma progression through the IL-6/STAT3 pathway. More importantly, HDFs pretreated with cyclosporine A or phenformin to induce ATF3 expression inhibited melanoma cell growth in vitro and in vivo. In summary, our study reveals that ATF3 suppresses human melanoma growth and that inducing the expression of ATF3 in HDFs can inhibit melanoma growth, a new potential melanoma therapeutic approach.https://www.frontiersin.org/article/10.3389/fonc.2020.00624/fullmelanomafibroblastsstromal cellsactivating transcription factor 3interleukin 6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tingjian Zu Tingjian Zu Jie Wen Jie Wen Lin Xu Lin Xu Lin Xu Hui Li Jun Mi Jun Mi Hui Li Cord Brakebusch David E. Fisher Xunwei Wu Xunwei Wu Xunwei Wu |
spellingShingle |
Tingjian Zu Tingjian Zu Jie Wen Jie Wen Lin Xu Lin Xu Lin Xu Hui Li Jun Mi Jun Mi Hui Li Cord Brakebusch David E. Fisher Xunwei Wu Xunwei Wu Xunwei Wu Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway Frontiers in Oncology melanoma fibroblasts stromal cells activating transcription factor 3 interleukin 6 |
author_facet |
Tingjian Zu Tingjian Zu Jie Wen Jie Wen Lin Xu Lin Xu Lin Xu Hui Li Jun Mi Jun Mi Hui Li Cord Brakebusch David E. Fisher Xunwei Wu Xunwei Wu Xunwei Wu |
author_sort |
Tingjian Zu |
title |
Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway |
title_short |
Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway |
title_full |
Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway |
title_fullStr |
Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway |
title_full_unstemmed |
Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway |
title_sort |
up-regulation of activating transcription factor 3 in human fibroblasts inhibits melanoma cell growth and migration through a paracrine pathway |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-04-01 |
description |
The treatment of melanoma has remained a difficult challenge. Targeting the tumor stroma has recently attracted attention for developing novel strategies for melanoma therapy. Activating transcription factor 3 (ATF3) plays a crucial role in regulating tumorigenesis and development, but whether the expression of ATF3 in human dermal fibroblasts (HDFs) can affect melanoma development hasn't been studied. Our results show that ATF3 expression is downregulated in stromal cells of human melanoma. HDFs expressing high levels of ATF3 suppressed the growth and migration of melanoma cells in association with downregulation of different cytokines including IL-6 in vitro. In vivo, HDFs with high ATF3 expression reduced tumor formation. Adding recombinant IL-6 to melanoma cells reversed those in vitro and in vivo effects, suggesting that ATF3 expression by HDFs regulates melanoma progression through the IL-6/STAT3 pathway. More importantly, HDFs pretreated with cyclosporine A or phenformin to induce ATF3 expression inhibited melanoma cell growth in vitro and in vivo. In summary, our study reveals that ATF3 suppresses human melanoma growth and that inducing the expression of ATF3 in HDFs can inhibit melanoma growth, a new potential melanoma therapeutic approach. |
topic |
melanoma fibroblasts stromal cells activating transcription factor 3 interleukin 6 |
url |
https://www.frontiersin.org/article/10.3389/fonc.2020.00624/full |
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