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Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development
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Journal Article
Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development
2017
Overview
TGF-β is known to influence tumour progression. Here we report an additional role of Smad3 in the tumour microenvironment regulating cancer progression. Deletion or inhibition of Smad3 in the tumour microenvironment suppresses tumour growth, invasion and metastasis in two syngeneic mouse tumour models. Smad3
−/−
bone marrow gives rise to an expanded NK cell population with enhanced tumour-suppressive activities
in vivo
, and promotes differentiation of NK cells
ex vivo
. We identify E4BP4/NFIL3 as a direct Smad3 target gene critical for NK cell differentiation. Smad3 suppresses transcription of IFN-γ via E4BP4 in a T-bet independent manner. Therefore disruption of Smad3 enhances both the E4BP4-mediated NK cell differentiation and anti-cancer effector functions
in vivo
and
in vitro
. Furthermore, systemic treatment with a Smad3 inhibitor SIS3 effectively suppresses cancer progression. In summary, suppression of NK cell-mediated immunosurveillance via the Smad3-E4BP4 axis contributes to cancer progression. We propose targeting Smad3-dependent tumour microenvironment may represent an effective anti-cancer strategy.
Smad3, a transcription factor activated by TGF-β, has been implicated in tumorigenesis. Here the authors show that Smad3 inhibits NK cell differentiation and effector function by repressing NFIL3, and that genetic or pharmacological blockade of Smad3 expands tumour-suppressive NK cells and restricts tumour growth in mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/109
/ 13/31
/ 13/51
/ 13/89
/ 13/95
/ 14/1
/ 14/5
/ 38/15
/ 38/77
/ 38/89
/ 59
/ 59/5
/ Animals
/ Basic-Leucine Zipper Transcription Factors - genetics
/ Basic-Leucine Zipper Transcription Factors - metabolism
/ Cancer
/ Cell Differentiation - immunology
/ Cells
/ Female
/ Humanities and Social Sciences
/ Isoquinolines - pharmacology
/ Killer Cells, Natural - immunology
/ Killer Cells, Natural - metabolism
/ Male
/ Melanoma
/ Neoplasms, Experimental - drug therapy
/ Neoplasms, Experimental - genetics
/ Neoplasms, Experimental - metabolism
/ Science
/ Smad3 Protein - antagonists & inhibitors
/ Tumors
