Development of lymphoproliferative diseases by hypoxia inducible factor-1alpha is associated with prolonged lymphocyte survival.
Development of lymphoproliferative diseases by hypoxia inducible factor-1alpha is associated with prolonged lymphocyte survival.
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DOI：
10.1371/journal.pone.0057833
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tanimoto K
中科院分区：
文献类型：
--
作者：
Sueoka E;Sueoka-Aragane N;Sato A;Ide M;Nakamura H;Sotomaru Y;Taya C;Yonekawa H;Kitagawa T;Kubota Y;Kimura S;Nakachi K;Tanimoto K
低氧诱导因子-1α(HIF-1α)在低氧耗氧相关基因的调控中起重要作用。据报道，HIF-1α的高表达与多种肿瘤的进展、侵袭和转移有关。为了探讨HIF-1α在肿瘤发生和转移中的作用，我们建立了在巨细胞病毒基因启动子调控下组成性表达HIF-1α基因的转基因小鼠。虽然不同器官HIF-1α蛋白水平不同，但大多数器官中HIF-1αmRNA的表达随着年龄的增加而逐渐增加。转基因小鼠在出生后8周内没有大体形态异常，尽管随后它们出现了淋巴、肺和乳房的肿瘤；最突出的肿瘤是出现在肠粘膜和间充质组织中的淋巴瘤。出生后13个月肿瘤患病率达80%。转基因小鼠的淋巴细胞群构成与野生型小鼠没有差异。然而，转基因小鼠的淋巴细胞在长期培养条件下存活时间延长，对细胞毒性依托泊苷的抵抗力增强。这些结果表明，HIF-1α本身不是致癌的，但在转基因小鼠模型中，它可能通过延长淋巴细胞的存活而在淋巴肿大中发挥重要作用。
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.
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