title: Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development.
abstract: 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.
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.|Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Patrick Ming-Kuen
authors.initials: PM
authors.lastname: Tang
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.|Clinical Translational Research Center, Shanghai Pulmonary Hospital, Shanghai 200092, China.|Department of Histology and Embryology, Tongji University School of Medicine, Tongji University Cancer Institute, Shanghai 200092, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Qing-Ming
authors.initials: QM
authors.lastname: Wang
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Chun-Jie
authors.initials: CJ
authors.lastname: Li
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Lian
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Tang
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Xin-Yuan
authors.identifier: 0000-0002-4485-6017
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Bryan Ping-Yen
authors.initials: BP
authors.lastname: Yan
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.|Li Ka Shing Institute of Health Sciences and Department of Medicine &Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; D050976:Basic-Leucine Zipper Transcription Factors; D007546:Isoquinolines; C497441:Nfil3 protein, mouse; D011725:Pyridines; D011758:Pyrroles; D051900:Smad3 Protein