title: PDCD4 Deficiency Aggravated Colitis and Colitis-associated Colorectal Cancer Via Promoting IL-6/STAT3 Pathway in Mice.
abstract: BACKGROUND
  Although programmed cell death (PDCD) 4 is generally considered to be a new tumor suppressor, the consequence of Pdcd4 deficiency in tumorigenesis is not well established. The role of PDCD4 in colitis-associated colorectal carcinoma (CRC) remains unknown.
  
  
  METHODS
  Experimental colitis and CRC were induced by dextran sodium sulfate and dextran sodium sulfate with azoxymethane, respectively, in wild type and Pdcd4 knockout (Pdcd4(-/-)) mice and were evaluated by clinical examination and histopathology. Levels of cytokines were detected by enzyme-linked immunosorbent assay. Changes in signaling pathways were examined by Western blot and immunofluorescent staining. Cell proliferation was determined by BrdU incorporation and Cell Counting Kit-8 staining.
  
  
  RESULTS
  Pdcd4 deficiency not only aggravated the dextran sodium sulfate-induced acute colitis but also promoted the development of colitis-induced CRC. Mechanically, Pdcd4 deficiency accelerated epithelial cell proliferation during tumorigenesis, markedly up-regulated the expression of proinflammatory cytokines, such as interleukin (IL)-6, and enhanced the activation of signal transducer and activator of transcription (STAT3), a IL-6 downstream effector. Using purified cells, we found that Pdcd4 deficiency increased IL-6 expression in vitro and the susceptibility to IL-6/STAT3 pathway-mediated cell proliferation significantly. Furthermore, blockade of IL-6/STAT3 pathway through sgp130Fc reversed the promoting effect of Pdcd4 deficiency on colonic epithelial cell proliferation in vivo.
  
  
  CONCLUSIONS
  The Pdcd4 deficiency accelerates colitis and colitis-associated CRC presumably through up-regulating IL-6/STAT3 pathway, suggesting that PDCD4 plays a protective role in inflammation-associated carcinoma and might be a potential target for the treatment of CRC.
authors.affiliation: *Department of Immunology, Shandong University School of Medicine, Jinan, China; and †Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.forename: Mingsheng
authors.initials: M
authors.lastname: Zhao
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.forename: Guannan
authors.initials: G
authors.lastname: Wang
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Shi
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D002273:Carcinogens; D016207:Cytokines; D015850:Interleukin-6; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; D001397:Azoxymethane