Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada.
Blood. 2011 Feb 10;117(6):2005-8. doi: 10.1182/blood-2010-02-271460. Epub 2010 Dec 8.
We have previously generated mice deficient for Nfe213 (NF-E2 p45 related factor 3 or Nrf3), a member of the cap 'n' collar family of basic-leucine zipper transcription factors. To examine whether Nrf3 is involved in chemical-induced carcinogenesis, we exposed the mice to benzo[a]pyrene (B[a]P), a carcinogen found in cigarette smoke. Contrary to wild-type mice, Nrf3-null animals are highly susceptible to B[a]P, exhibiting significantly increased mortality. Pathology analysis of affected tissue sections revealed a high incidence of T-cell lymphoblastic lymphoma in B[a]P-treated Nrf3(-/-) mice. Lymphoblastic lymphoma occasionally metastasized into the lung as demonstrated by perivascular malignant lymphocytic infiltration. Together, our studies show that the absence of Nrf3 predisposes mice to lymphoma development, suggesting a protective role of this transcription factor in hematopoietic malignancies. Our data demonstrate the first in vivo function of Nrf3 and its link to tumor development. Nrf3-deficient mice may serve as a preclinical mouse model to study carcinogen-induced lymphomagenesis.
我们先前生成了 Nfe213（NF-E2 p45 相关因子 3 或 Nrf3）缺失的小鼠，Nfe213 是一个基本亮氨酸拉链转录因子的“cap 'n' collar”家族成员。为了研究 Nrf3 是否参与化学诱导的致癌作用，我们使这些小鼠接触苯并[a]芘（B[a]P），一种香烟烟雾中发现的致癌物质。与野生型小鼠相反，Nrf3 缺失型动物对 B[a]P 非常敏感，死亡率显著增加。受影响组织切片的病理学分析显示，B[a]P 处理的 Nrf3（-/-）小鼠中 T 细胞淋巴母细胞淋巴瘤的发生率很高。淋巴母细胞淋巴瘤偶尔会转移到肺部，如血管周围恶性淋巴样浸润所示。总之，我们的研究表明，Nrf3 的缺失使小鼠易发生淋巴瘤，表明该转录因子在造血恶性肿瘤中具有保护作用。我们的数据表明 Nrf3 的第一个体内功能及其与肿瘤发展的联系。Nrf3 缺失型小鼠可能作为一种临床前小鼠模型，用于研究致癌物诱导的淋巴瘤发生。
