title: Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression.
abstract: BACKGROUND
  Hypoxia-inducible factor 1 alpha (HIF-1alpha) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1alpha during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas.
  
  
  METHODS
  Immunohistochemistry and Western blot is used to analyse HIF-1alpha expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1alpha inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry.
  
  
  RESULTS
  In normal mucosa, HPP and TA-LGD HIF-1alpha was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1alpha were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1alpha overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1alpha expression was strongly accumulated in perinecrotic regions. In these cases HIF-1alpha activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1alpha was also seen in periinflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1alpha expression and nuclear translocation.
  
  
  CONCLUSIONS
  We conclude that HIF-1alpha expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic activation of HIF-1alpha in invasive tumors underlines a dual role of HIF-1alpha by regulating both pro-survival and pro-death processes. HIF-1alpha up-regulation in response to LPS-mediated stimulation and periinflammatory expression in invasive carcinomas suggest its involvement in inflammatory events. These patterns of HIF-1alpha inducibility could contribute indirectly to the acquisition of a metastatic phenotype.
authors.affiliation: Institute of Pathology, Johannes Gutenberg University Mainz, Germany. simiantonaki@yahoo.de
authors.forename: Nektaria
authors.initials: N
authors.lastname: Simiantonaki
authors.forename: Marios
authors.initials: M
authors.lastname: Taxeidis
authors.forename: Caren
authors.initials: C
authors.lastname: Jayasinghe
authors.forename: Ursula
authors.initials: U
authors.lastname: Kurzik-Dumke
authors.forename: Charles James
authors.initials: CJ
authors.lastname: Kirkpatrick
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D003111:Colonic Polyps / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D009362:Neoplasm Metastasis; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides