title: Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer.
abstract: Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle- and apoptosis-control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF-1-dependent. Our aim was to evaluate the expression of the HIF-1alpha, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF-1alpha expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF-1alpha-negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF-1alpha, p53 and p21 and proliferation and apoptosis. HIF-1alpha overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF-1alpha, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF-1alpha) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT.
authors.affiliation: Department of General Surgical Science, Gunma University Faculty of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. msohda@med.gunma-u.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Sohda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Norihiro
authors.initials: N
authors.lastname: Masuda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nakajima
authors.forename: Minoru
authors.initials: M
authors.lastname: Fukuchi
authors.forename: Ryokuhei
authors.initials: R
authors.lastname: Manda
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fukai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009361:Neoplasm Invasiveness / Q000473:pathology; D011237:Predictive Value of Tests; D014157:Transcription Factors / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D016335:Zinc Fingers
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C087628:TCEAL1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53