title: Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer.
abstract: Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6-deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6-deficient mice were significantly smaller. Notably, both the lung tumor-suppressing and -promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. xiaog2@upmc.edu quz@upmc.edu.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Qu
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Fan
authors.initials: F
authors.lastname: Sun
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jingjiao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Liwen
authors.initials: L
authors.lastname: Li
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. xiaog2@upmc.edu quz@upmc.edu.
authors.forename: Gutian
authors.initials: G
authors.lastname: Xiao
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015870:Gene Expression; D006706:Homeostasis; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D018345:Mice, Knockout; D009154:Mutation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins
chemical_list: D018925:Chemokines; D015850:Interleukin-6; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D019938:Cyclin D1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins