Korean J Hepatol > Volume 16(3); 2010 > Article
Kim: Hypoxia-inducible factor 1, hepatocellular carcinoma and angiogenesis
See Article on Page 280
Angiogenesis is essential for tumor growth,1 and it has been shown that anti-angiogenic therapy has been proven to be effective in several cancers such as colorectal cancer2,3 and hepatocellular carcinoma (HCC).4 Currently available antiangiogenic cancer chemotherapy targets the vascular endothelial growth factor (VEGF) pathway by VEGF monoclonal antibody (bevacizumab)3 or multi-targeted receptor tyrosine kinase inhibitors (sorafenib).4 Hypoxia-inducible factor 1 (HIF-1) is a heterodimer protein which is composed of oxygen-regulated HIF-1α subunit and constitutively expressed HIF-1β subunit.5,6 Under normoxic condition, the degradation of HIF-1α subunit is facilitated by ubiquitination following the hydroxylation of proline residue(s). However, under hypoxic condition, stability of HIF-1α increases due to suppressed proline hydroxylation, leading to increased transcription of genes associated with adaptive homeostatic response to hypoxia such as erythropoiesis, glucose metabolism and angiogenesis.7 In addition to intratumoral hypoxia, loss of function of tumor-suppressor genes also contributes to over-expression of HIF-1α in various human cancers.6 HIF-1 is a key regulatory factor for angiogenesis in response to hypoxia: it induces expression of angiogenic growth factors such as VEGF, stromal derived factor 1, angiopoietin 2, placental growth factor, platelet-derived growth factor B and stem cell factor.8 Many human cancers over-express HIF-1α, and expression of HIF-1α is associated with poor prognosis.6,9 In hepatitis B virus-associated HCC, high expression of HIF-1α is found in half of tumor specimens and correlated with venous invasion and lymph node invasion.10 These findings suggest the possibility of HIF-1α as a novel therapeutic target in HCC.
In the current issue, Choi et al. suppressed HIF-1α by adenovirus-mediated small hairpin RNA and observed that proliferation of hepatoma cell lines was suppressed and the new vessel formation by vascular endothelial cells was inhibited.11 This suppressive effect against hepatoma cells is concordant with the report by WeiXing et al. which knocked down HIF-1α by antisense oligonucleotide.12 In the current study, however, the mechanisms by which HIF-1α directly inhibits the proliferation of hepatoma cell lines were not examined. In hypoxic state, HIF-1 can either induce or inhibit apoptosis.13 Moreover, a recent report shows that knock-down of HIF-1α causes reciprocal increase of HIF-2α and vice versa, leading to attenuated apoptosis in HepG2 cells.14 Therefore, further studies are warranted to examine the effects of HIF-1α on the apoptosis and proliferation of HCC in hypoxic state.
Recent reports including this study by Choi et al. have demonstrated that knock-down of HIF-1α by small interfering RNA15 or short hairpin RNA can disrupt angiogenesis by HUVEC cells. However, the therapeutic potential of anti-angiogenic effect by targeting HIF-1 needs to be further validated in animal HCC models. One recent study targeting HIF-1α showed suppressed tumor growth and microvessel density in a murine subcutaneous HCC model.16 However, two reports assessing the effect of HIF-1α on the tumor growth in orthotopic hepatoma models showed conflicting results.17,18 These results imply that the action of HIF-1 may be influenced by the types of tumor cells and/or the stromal components of the tumor.9 Further animal studies are also warranted to examine the efficacy of combination therapy that includes HIF-1α targeting and conventional types of anti-cancer drugs.

REFERENCES

1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186. 4938153.
crossref pmid
2. Wagner AD, Arnold D, Grothey AA, Haerting J, Unverzagt S. Anti-angiogenic therapies for metastatic colorectal cancer. Cochrane Database Syst Rev 2009;3:CD005392. 19588372.

3. Reinacher-Schick A, Pohl M, Schmiegel W. Drug insight: antiangiogenic therapies for gastrointestinal cancers-focus on monoclonal antibodies. Nat Clin Pract Gastroenterol Hepatol 2008;5:250-267. 18382435.
crossref pmid
4. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390. 18650514.
crossref pmid
5. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510-5514. 7539918.
crossref pmid pmc
6. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2010;29:625-634. 19946328.
crossref pmid pmc
7. Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 2009;24:97-106. 19364912.
crossref pmid
8. Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 2010;86:236-242. 20164116.
crossref pmid pmc
9. Melillo G. Inhibiting hypoxia-inducible factor 1 for cancer therapy. Mol Cancer Res 2006;4:601-605. 16940159.
crossref pmid
10. Xie H, Song J, Liu K, Ji H, Shen H, Hu S, et al. The expression of hypoxia-inducible factor-1alpha in hepatitis B virus-related hepatocellular carcinoma: correlation with patients' prognosis and hepatitis B virus X protein. Dig Dis Sci 2008;53:3225-3233. 18465238.
crossref pmid
11. Choi SH, Shin HW, Park JY, Yoo JY, Kim DY, Rho WS, et al. Effects of the knockdown of hypoxia inducible factor-1alpha expression by adenovirus-mediated shRNA on angiogenesis and tumor growth inhibition in hepatocellular carcinoma cell lines. Korean J Hepatol 2010;16:280-287. 20924210.
crossref pmid pmc
12. WeiXing C, Tiantian H, Qun N, Chaohui Y, Ping X. Inhibitory effect of hypoxia inducible factor-1 antisense oligonucleotide on growth of human hepatocellular carcinoma cells. Med Oncol 2008;25:88-92. 18188720.
crossref pmid
13. Greijer AE, van der Wall E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 2004;57:1009-1014. 15452150.
crossref pmid pmc
14. Menrad H, Werno C, Schmid T, Copanaki E, Deller T, Dehne N, et al. Roles of hypoxia-inducible factor-1alpha (HIF-1alpha) versus HIF-2alpha in the survival of hepatocellular tumor spheroids. Hepatology 2010;51:2183-2192. 20513003.
crossref pmid
15. Jiang J, Xia XB, Xu HZ, Xiong Y, Song WT, Xiong SQ, et al. Inhibition of retinal neovascularization by gene transfer of small interfering RNA targeting HIF-1alpha and VEGF. J Cell Physiol 2009;218:66-74. 18767037.
crossref pmid
16. Liu F, Wang P, Jiang X, Tan G, Qiao H, Jiang H, et al. Antisense hypoxia-inducible factor 1alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma. Cancer Sci 2008;99:2055-2061. 19016766.
pmid
17. Sun X, Jiang H, Jiang X, Tan H, Meng Q, Sun B, et al. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther 2009;20:314-324. 19327024.
crossref pmid
18. Daskalow K, Rohwer N, Raskopf E, Dupuy E, Kuhl A, Loddenkemper C, et al. Role of hypoxia-inducible transcription factor 1 alpha for progression and chemosensitivity of murine hepatocellular carcinoma. J Mol Med 2010;88:817-827. 20383692.
crossref pmid

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 672
TOTAL : 829131
Close layer