Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
PLoS One. 2013 Apr 12;8(4):e57833. doi: 10.1371/journal.pone.0057833. Print 2013.
Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.
缺氧诱导因子-1α（HIF-1α）在调节与低氧消耗相关的各种基因中发挥着重要作用。在许多癌症中，HIF-1α的高表达与肿瘤的进展、侵袭和转移有关。为了研究 HIF-1α在肿瘤发生和转移中的作用，我们建立了一种转基因小鼠，其 HIF1A 基因在巨细胞病毒基因启动子的调控下持续表达。虽然 HIF-1α 蛋白水平在不同器官之间存在差异，但大多数器官中的 HIF1A mRNA 表达水平随年龄的增长呈逐渐增加的趋势。这些转基因小鼠在出生后 8 周内没有明显的大体形态异常，但随后在淋巴、肺和乳腺中出现肿瘤；最突出的肿瘤是淋巴瘤，出现在肠黏膜和间质组织中。在出生后 13 个月时，肿瘤的发生率达到 80%。转基因小鼠的淋巴细胞群组成与野生型小鼠没有差异。然而，在长期培养条件下，转基因小鼠的淋巴细胞存活时间延长，对细胞毒药物依托泊苷的耐药性增强。这些结果表明，HIF-1α 本身不是致癌的，但它可能通过延长这种转基因小鼠模型中淋巴细胞的存活，在淋巴瘤的发生中发挥重要作用。
