title: IL-10 promotes tumor aggressiveness via upregulation of CIP2A transcription in lung adenocarcinoma.
abstract: OBJECTIVE
  Interleukin-10 (IL-10) determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial.
  
  
  METHODS
  To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10-mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were conducted. IL-10 and CIP2A mRNA levels in lung tumors from patients with lung cancer were determined by real-time reverse transcription PCR. The prognostic value of both molecules on survival was estimated by Cox regression model.
  
  
  RESULTS
  Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6 knockdown TL1 cells and increased in E6- overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of cAMP response element-binding protein (CREB) and C/enhancer-binding protein β (C/EBPβ) via phosphoinositide 3-kinase (PI3K) signaling pathway. IL-10-mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors.
  
  
  CONCLUSIONS
  IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients' outcome and life quality.
authors.affiliation: School of Medicine, Chung Shan Medical University Hospital, Taiwan, China.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Sung
authors.forename: Yao-Chen
authors.initials: YC
authors.lastname: Wang
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Lin
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Cheng
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Tzu-Chin
authors.initials: TC
authors.lastname: Wu
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D001324:Autoantigens; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D019869:Phosphatidylinositol 3-Kinases; D012097:Repressor Proteins; C500266:CIP2A protein, human; C068651:E6 protein, Human papillomavirus type 16; C508609:IL10 protein, human