title: Hypoxia-inducible factor-1 up-regulates the expression of Toll-like receptor 4 in pancreatic cancer cells under hypoxic conditions.
abstract: OBJECTIVE
  Hypoxia is a common characteristic of solid tumors. Recent studies confirmed that Toll-like receptor 4 (TLR4) plays a significant role in cancer invasion and progression. In this study, the correlation between the expression of TLR4 and the change of the protein level of Hypoxia-inducible factor-1 alpha (HIF-1α) was studied.
  
  
  METHODS
  We examined 84 human pancreatic cancer tissues for expression of HIF-1α and TLR4 proteins. Panc-1 cells were exposed to normoxia (20% O(2)) or hypoxia (<1% O(2)) or treated with CoCl(2). TLR4 protein was analyzed by flow cytometry and immunostaining. Growth studies were conducted on cells with the HIF-1α inhibition isolated from stable transfected cell lines. Finally, TLR4 protein was detected by immunohistochemistry in vivo tumors.
  
  
  RESULTS
  There was a positive correlation between TLR4 and HIF-1α protein in pancreatic cancer tissues. Hypoxic stress induced TLR4 mRNA and protein expression in Panc-1 cells. Cells transfected with HIF-1α siRNA showed attenuation of hypoxia stress-induced TLR4 expression. In vivo growth decreased in response to TLR4 and HIF-1α inhibiton. Transient HIF-1α siRNA treatment could effectively curb tumor growth in vivo.
  
  
  CONCLUSIONS
  These results suggest that TLR4 expression in pancreatic cancer cells is up-regulated via HIF-1α in response to hypoxic stress and underscore the crucial role of HIF-1α-induced TLR4 in tumor growth.
authors.affiliation: Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang Road, Wuhan, Hubei 430022, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Han-Qing
authors.initials: HQ
authors.lastname: Wu
authors.forename: Si-Xing
authors.initials: SX
authors.lastname: Zhou
authors.forename: Chun-You
authors.initials: CY
authors.lastname: Wang
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: He-Shui
authors.initials: HS
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D018384:Oxidative Stress; D010100:Oxygen / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003035:Cobalt; C018021:cobaltous chloride; D010100:Oxygen