Role of hypoxia inducible factor-1α in renal cancer

缺氧诱导因子-1α (HIF-1α)是一种调控参与缺氧反应的基因的转录因子。为了明确其在肿瘤生长和进展中的作用，我们建立了过表达hif -1α的肾癌VMRC细胞（VMRC- hif1 α细胞）和膀胱癌EJ细胞（EJ- hif1 α细胞），并将其与VMRC-neo和EJ-neo对照细胞的特征进行了比较。体外研究表明，HIF-1α在VMRC和EJ细胞中的过表达可减轻细胞增殖的接触抑制，并使这些细胞抵抗缺氧应激。我们进一步检测了裸鼠体内的致瘤性。四种类型的癌细胞（VMRC-neo细胞、VMRC-HIF1α细胞、EJ-neo细胞和EJ-HIF1α细胞）在裸鼠体内均形成肿瘤，并且VMRC-HIF1α细胞来源的异种移植物的大小远大于VMRC-neo细胞。虽然HIF-1α过表达不影响EJ细胞来源的异种移植物的大小，但组织学检查显示，EJ- HIF-1α细胞来源的异种移植物中只有小面积的坏死，而EJ-neo细胞来源的异种移植物中观察到大面积的中心坏死。我们还发现HIF-1α过表达增加了异种移植物瘤内微血管密度。提示HIF-1α可能在膀胱癌和肾癌血管生成、生长和进展中发挥重要作用。

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.