Role of hypoxia inducible factor-1α in renal cancer

缺氧诱导因子-1 α（Hypoxia-inducible factor-1α，HIF-1α）是一种转录因子，可调节参与缺氧反应的基因。为了阐明HIF-1 α在肿瘤生长和进展中的作用，我们建立了HIF-1α过表达的肾细胞癌VMRC细胞（VMRC-HIF 1 α细胞）和膀胱癌EJ细胞（EJ-HIF 1 α细胞），并将其特性与VMRC-neo和EJ-neo对照细胞进行比较。体外研究表明，HIF-1α在VMRC和EJ细胞中的过表达解除了细胞增殖的接触抑制，并使这些细胞对缺氧应激具有抗性。我们进一步研究了裸鼠体内致瘤性。所有四种类型的癌细胞（VMRC-neo细胞、VMRC-HIF 1 α细胞、EJ-neo细胞和EJ-HIF 1 α细胞）在裸鼠中形成肿瘤，并且VMRC-HIF 1 α细胞衍生的异种移植物的大小远大于VMRC-neo细胞。尽管HIF-1α过表达并不影响EJ细胞来源的异种移植物的大小，但组织学检查显示，在EJ-HIF-1 α细胞来源的异种移植物中仅观察到小面积的坏死，而在EJ-neo细胞来源的异种移植物中观察到大面积的中央坏死。还发现HIF-1α过表达增加异种移植物中肿瘤内微血管密度。提示HIF-1α可能在膀胱癌和肾癌的血管生成、生长和进展中起重要作用。

Hypoxia-inducible factor-1α, HIF-1α, is a transcriptional factor that regulates genes involved in the response to hypoxia. To clarify its roles in tumour growth and progression, we established HIF-1α-overexpressing renal cell carcinoma VMRC cells (VMRC-HIF1α cells) and bladder cancer EJ cells (EJ-HIF1α cells) and compared their characteristics with VMRC-neo and EJ-neo control cells. In vitro studies showed that overexpression of HIF-1α in both VMRC and EJ cells relieves the contact inhibition of cell proliferation and renders these cells resistant to hypoxic stress. We further examined in vivo tumourigenicity in nude mice. All four types of cancer cells (VMRC-neo cells, VMRC-HIF1α cells, EJ-neo cells, and EJ-HIF1α cells) formed tumours in nude mice, and the size of VMRC-HIF1α cell-derived xenografts was much larger than that of VMRC-neo cells. Although HIF-1α overexpression did not affect the size of EJ cell-derived xenografts, histological examination showed that there was only a small area of necrosis in the EJ-HIF1α cell-derived xenografts whereas a large area of central necrosis was observed in the EJ-neo cell-dereived xenografts. It was also found that HIF-1α overexpression increased intratumoural microvessel density in the xenografts. These results suggest that HIF-1α may play important roles in bladder and renal cancer angiogenesis, growth and progression.