title: Promotion of lung tumor growth by interleukin-17.
abstract: Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro- and antitumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-Ras(LA1) mice) with lung delivery of a recombinant adenovirus that expresses IL-17A. Virus-mediated expression of IL-17A in K-Ras(LA1) mice at 8-10 wk of age doubled lung tumor growth in 3 wk relative to littermates that received a green fluorescent protein-expressing control adenovirus. IL-17 induced matrix metalloproteinase-9 (MMP-9) expression in vivo and in vitro. In accord with this finding, selective and specific inhibitors of MMP-9 repressed the increased motility and invasiveness of IL-17-treated lung tumor cells in culture. Knockdown or mutation of p53 promoted the motility of murine lung tumor cells and abrogated the promigratory role of IL-17. Coexpression of siRNA-resistant wild-type, but not mutant, human p53 rescued both IL-17-mediated migration and MMP-9 mRNA induction in p53 knockdown lung tumor cells. IL-17 increased MMP-9 mRNA stability by reducing interaction with the mRNA destabilizing serine/arginine-rich splicing factor 1 (SRSF1). Taken together, our results indicate that IL-17 stimulates lung tumor growth and regulates MMP-9 mRNA levels in a p53- and SRSF1-dependent manner.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana;
authors.forename: Beibei
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana;
authors.forename: James F
authors.initials: JF
authors.lastname: Guenther
authors.affiliation: Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Pociask
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana;
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Structural and Cellular Biology, Tulane University, New Orleans, Louisiana;
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
authors.affiliation: Heart and Vascular Insitute, Tulane University, New Orleans, Louisiana; and.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
authors.affiliation: Department of Medicine-Pulmonary Section, Tulane University, New Orleans, Louisiana;
authors.forename: Bin
authors.initials: B
authors.lastname: Shan
authors.affiliation: Department of Microbiology, Tulane University, New Orleans, Louisiana;
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Sullivan
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana; gmorris2@tulane.edu.
authors.forename: Gilbert F
authors.initials: GF
authors.lastname: Morris
mesh_terms: D000818:Animals; D002465:Cell Movement; D004795:Enzyme Stability / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C541926:Gm6687 protein, mouse; C508717:IL17A protein, human; C098680:Il17a protein, mouse; D020381:Interleukin-17; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000068103:Serine-Arginine Splicing Factors; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: IL-17; MMP-9; SRSF1; lung tumor growth; p53