title: Overexpression of hypoxia inducible factor-1 alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases.
abstract: BACKGROUND
  Hypoxia inducible factor-1α (HIF-1α) is a major regulator of tumorigenesis in hypoxic conditions and therefore represents a potential therapeutic target in colorectal cancer (CRC). Clinical significance of HIF-1α expression in liver metastases has not been elucidated. Therefore, this study aimed to clarify the clinical significance of HIF-1α expression in colorectal liver metastasis (CRLM).
  
  
  METHODS
  We retrospectively analyzed 64 patients who underwent curative resection of CRLM from 2000 to 2008. We evaluated HIF-1α expression by immunohistochemical staining and analyzed its association with several clinicopathological characteristics, including vascular endothelial growth factor (VEGF) expression. We analyzed the mutation status of genes involved in CRC (p53, KRAS, BRAF, and PIK3CA). Finally, we compared HIF-1α expression between the primary tumor and the corresponding liver metastases.
  
  
  RESULTS
  We found a significant positive correlation between HIF-1α expression in liver metastases and PIK3CA mutation status (p = 0.019). A significant correlation was also observed between the expressions of HIF-1α and VEGF in liver metastases and primary tumors (p = 0.015, 0.024, respectively). High HIF-1α expression in liver metastases was an independent risk factor for recurrence (p = 0.031).
  
  
  CONCLUSIONS
  Our results suggest a possible induction of HIF-1α expression by mutant PIK3CA. The expressions of HIF-1α and VEGF in liver metastases significantly correlated with those in the corresponding primary tumor. Overexpression of HIF-1α was an independent risk factor for recurrence after curative resection of CRLM, suggesting that HIF-1α represents an important candidate for the treatment of CRLM in a subset of patients with high HIF-1α expression.
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Shimomura
authors.forename: Takao
authors.initials: T
authors.lastname: Hinoi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kuroda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Adachi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Tatsunari
authors.initials: T
authors.lastname: Sasada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takakura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Egi
authors.forename: Masazumi
authors.initials: M
authors.lastname: Okajima
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tashiro
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishizaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006498:Hepatectomy / Q000009:adverse effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit