Hypoxia-inducible factor 1, hepatocellular carcinoma and angiogenesis

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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.