Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma
Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma
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DOI：
10.1111/liv.12375
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发表时间：
2014-04-01
影响因子：
6.7
通讯作者：
Han, Kwang-Hyub
中科院分区：
文献类型：
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作者：
Choi, Sung Hoon;Kwon, Oh-Joon;Han, Kwang-Hyub
背景与目的缺氧诱导因子-1 α（HIF-1 α）是细胞对缺氧反应的关键转录因子，白细胞介素8（IL-8）是血管生成的关键介质，在肿瘤生长中起重要作用。在这项研究中，我们评估了HIF-1 α和IL-8敲低对肝细胞癌（HCC）血管生成和肿瘤生长的影响。方法用表达HIF-1 α或IL-8特异性小发夹RNA（shRNA）的腺病毒感染肝细胞癌细胞系，在缺氧条件下（1%O2）培养，并检测其HIF-1 α，IL-8，和血管生成因子。腺病毒介导的shRNA诱导的HIF-1 α和IL-8敲低对肿瘤生长和血管生成的影响也进行了研究，在皮下Hep 3B肿瘤mouse model.ResultsHypoxia-inducible factor-1 α敲低直接抑制肿瘤生长，而IL-8敲低间接抑制肿瘤生长。HIF-1 α和IL-8的联合敲低增加了小鼠的存活率。HIF-1 α和IL-8敲低也降低了体内微血管密度和肿瘤体积。同样，HIF-1 α和IL-8敲低抑制血管生成的影响，肝癌细胞条件培养基管的形成和入侵的内皮cells in vitro.ConclusionThese研究结果表明，shRNA诱导的HIF-1 α和IL-8敲低抑制血管生成和肿瘤生长在肝癌。HIF-1 α和IL-8 shRNA技术的进一步发展可能会导致HCC的有效治疗。
Background & AimsHypoxia-inducible factor-1 alpha (HIF-1 alpha), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL-8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF-1 alpha and IL-8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC).MethodsHepatocellular carcinoma cell lines were infected with adenoviruses expressing small-hairpin RNA (shRNA) specific for HIF-1 alpha or IL-8, cultured under hypoxic conditions (1% O2), and examined for their levels of HIF-1 alpha, IL-8, and angiogenesis factors using immunoblot. The effects of adenovirus-mediated shRNA-induced HIF-1 alpha and IL-8 knockdown on tumour growth and angiogenesis were also investigated in a subcutaneous Hep3B-tumour mouse model.ResultsHypoxia-inducible factor-1 alpha knockdown directly repressed tumour growth, whereas IL-8 knockdown indirectly repressed tumour growth. Combined knockdown of HIF-1 alpha and IL-8 increased survival rates of mice. HIF-1 alpha and IL-8 knockdown also decreased microvessel density and tumour volume in vivo. Similarly, HIF-1 alpha and IL-8 knockdown inhibited the angiogenic effects of HCC cell-conditioned media on tube formation and invasion by endothelial cells in vitro.ConclusionThese findings indicate that shRNA-induced HIF-1 alpha and IL-8 knockdown inhibit angiogenesis and tumour growth in HCC. Further development of HIF-1 alpha and IL-8 shRNA technologies could lead to effective therapies for HCC.