title: HIF-1alpha is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy.
abstract: Among several chemotherapeutic agents, 5-fluorouracil (5-FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5-FU in an adjuvant setting, has been identified. Hypoxia-induced drug resistance, via upregulation of HIF-1alpha, is a major obstacle in the development of effective cancer therapy. However, few clinical studies have so far assessed the relationship between the HIF-1alpha expression and the chemo-resistance of gastric cancer patients in an adjuvant setting. We established 2 HIF-1alpha knockdown gastric cancer cell lines in order to clarify the role of HIF-1alpha in chemo-resistance against 5-FU. Furthermore, expression of HIF-1alpha was immunohistochemically assessed in 91 resected specimens. Sixty-four of 91 patients received 5-FU adjuvant chemotherapy after surgery. HIF-1alpha expression was associated with the significantly shorter relapse-free survival and disease-specific survival in the 64 patients of adjuvant group (p = 0.026, 0.014, respectively), but not in the 27 of surgery group. Multivariate analysis showed that HIF-1alpha was an independent risk factor for relapse in 64 patients in the adjuvant group (p = 0.029). In conclusion, the current study confirmed, for the first time that HIF-1alpha expression is an independent risk factor for relapse in high-risk gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. A favorable effect of 5-FU might therefore be expected in patients that do not express HIF-1alpha, whereas, other types of chemotherapy or additional treatments, such as HIF-1alpha inhibitors, should be considered in patients that do express HIF-1alpha.
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kitajima
authors.forename: Keita
authors.initials: K
authors.lastname: Kai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hashiguchi
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hiraki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Noshiro
authors.forename: Kohji
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D005472:Fluorouracil