Hypoxia-induced up-regulation of angiogenin, besides VEGF, is related to progression of oral cancer

Koji Kishimoto, Shoko Yoshida, Soichiro Ibaragi, Norie Yoshioka, Tatsuo Okui, Guo Fu Hu, Akira Sasaki

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


Objectives: Angiogenin (ANG) is a prominent angiogenic factor that has been shown to have a dual effect on tumor progression by inducing both angiogenesis and cancer cell proliferation through stimulating ribosomal RNA transcription in both endothelial cells and cancer cells. In the present study, we investigated the expression profiles of ANG and vascular endothelial growth factor (VEGF) in oral cancer and their correlation with hypoxia and evaluated the possible value of ANG as a therapeutic target for oral cancer. Materials and Methods: Immunohistochemistry (IHC), ELISA, real-time RT-PCR and Western blotting were used to examine the expression of ANG, VEGF, and hypoxia-inducible factor 1α (HIF-1α) in oral squamous cell carcinoma (OSCC) specimens and human OSCC cell lines. In order to examine the role of ANG, we knocked down ANG expression in HSC-2 cells by means of plasmid-mediated RNA interference. Results: IHC showed that the expression of ANG was significantly correlated with that of HIF-1α in 50 OSCC specimens (P = 0.031). However, no significant correlation between VEGF and HIF-1α expression was found (P = 0.243). Consistently, ANG secretion increased under hypoxia in all of the 10 OSCC cell lines tested; and a significant increase was observed in 6 of them. In contrast, there was no noticeable increase in VEGF secretion under hypoxia in any of these cell lines. In HSC-2 and SAS OSCC cells, the increase in ANG mRNA expression correlated very well with that of HIF-1α protein expression after hypoxia onset. However, no noticeable increase in VEGF mRNA expression was observed even after 12 h of hypoxia. Down-regulation of ANG expression in HSC-2 cells highly expressing and secreting VEGF inhibited ribosome biogenesis, cell proliferation, tumor angiogenesis, and xenograft growth in athymic mice. Conclusion: These results suggest that ANG is up-regulated in the hypoxic environment of oral cancers and that its inhibition can have a therapeutic implication.

Original languageEnglish
Pages (from-to)1120-1127
Number of pages8
JournalOral Oncology
Issue number11
Publication statusPublished - Nov 2012


  • Angiogenesis
  • Angiogenin
  • Cell proliferation
  • Hypoxia
  • Hypoxia-inducible factor 1α (HIF-1α)
  • Oral cancer
  • Ribosome biogenesis
  • Vascular endothelial growth factor (VEGF)

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research


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