Promotion of Liver and Lung Tumorigenesis in DEN-Treated Cytoglobin-Deficient Mice
Promotion of Liver and Lung Tumorigenesis in DEN-Treated Cytoglobin-Deficient Mice
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DOI：
10.1016/j.ajpath.2011.05.006
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发表时间：
2011-08-01
影响因子：
6
通讯作者：
Kawada, Norifumi
中科院分区：
文献类型：
--
作者：
Le Thi Thanh Thuy;Morita, Takashi;Kawada, Norifumi
细胞珠蛋白（Cygb）是最近发现的一种脊椎动物珠蛋白，具有与肌红蛋白相似的分子特征。为了研究Cygb在体内的生物学功能，我们产生了Cygb基因敲除小鼠，并研究了它们对N，N-二乙基亚硝胺（DEN）诱导的肿瘤发生的易感性。4周龄的雄性小鼠在饮用水中以25 ppm的剂量给予DEN 25周或0.05 ppm的剂量给予DEN 36周。Cygb缺乏促进DEN诱导的肝和肺肿瘤的发展。所有接受25 ppm DEN治疗的Cygb（+/-）和Cygb（-/-）小鼠均出现肝脏肿瘤，而野生型小鼠的这一比例为44.4%。肺肿瘤仅存在于Cygb缺陷小鼠中。超过40%的Cygb（-/-）小鼠在无毒剂量的DEN（0.05 ppm）下发生肝和肺肿瘤，而DEN在野生型小鼠中不会诱导肿瘤。Cygb丢失与癌细胞增殖增加、细胞外信号调节激酶和Akt活化升高、IL-1 β、IL-6、TNF α和TGF β 3 mRNA过表达以及肝胶原积累相关。Cygb缺陷小鼠还表现出硝基酪氨酸形成增加和癌症相关基因（细胞周期蛋白D2，p53，Pak1，Src，Cdkn2a和Cebpa）表达失调。这些结果表明，Cygb缺乏诱导暴露于DEN的小鼠的肝脏和肺中的癌症发展的易感性。因此，球蛋白如Cygb将揭示新的器官癌变的生物学特征。(Am J Pathol 2011，179：1050 - 1060; DOI：10.1016/j.ajpath.2011.05.006）
Cytoglobin (Cygb) is a recently discovered vertebrate globin with molecular characteristics that are similar to myoglobin. To study the biological function of Cygb in vivo, we generated Cygb knockout mice and investigated their susceptibility to N,N-diethylnitrosamine (DEN)-induced tumorigenesis. Four-week-old male mice were administered DEN in drinking water at a dose of 25 ppm for 25 weeks or 0.05 ppm for 36 weeks. Cygb deficiency promoted the DEN-induced development of liver and lung tumors. All Cygb(+/-) and Cygb(-/-) mice treated with 25-ppm DEN exhibited liver tumors, compared with 44.4% of their wild-type counterparts. Lung tumors were present only in Cygb-deficient mice. More than 40% of Cygb(-/-) mice developed liver and lung tumors at the nontoxic dose of DEN (0.05 ppm), which did not induce tumors in wild-type mice. Cygb loss was associated with increased cancer cell proliferation, elevated extracellular signal-regulated kinase and Akt activation, overexpression of IL-1 beta, IL-6, Tnf alpha, and Tgf beta 3 mRNAs, and hepatic collagen accumulation. Cygb-deficient mice also exhibited increased nitrotyrosine formation and dysregulated expression of cancer-related genes (cyclin D2, p53, Pak1, Src, Cdkn2a, and Cebpa). These results suggest that Cygb deficiency induces susceptibility to cancer development in the liver and lungs of mice exposed to DEN. Thus, globins such as Cygb will shed new light on the biological features of organ carcinogenesis. (Am J Pathol 2011, 179:1050-1060; DOI: 10.1016/j.ajpath.2011.05.006)