Lung tumors in mice expressing an antisense RAR beta 2 transgene
Lung tumors in mice expressing an antisense RAR beta 2 transgene
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DOI：
10.1096/fasebj.10.9.8801172
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发表时间：
1996-07-01
期刊：
影响因子：
4.8
通讯作者：
Bradley, WEC
中科院分区：
文献类型：
--
作者：
Berard, J;Laboune, F;Bradley, WEC
视黄酸已被证明是一种抗癌剂，越来越多的文献表明，它是核视黄酸受体β 2（RAR β 2），主要负责介导这种效果，至少在某些系统中，为了确定是否部分失活RAR β 2将在小鼠中易患肺癌，我们产生了三个转基因系表达反义序列。当在13-3/4-18月龄时处死时，21/36只动物在尸检时具有总共43个表面可见的肺肿瘤，而在23只非转基因小鼠中，仅1只具有单个可见的肺肿瘤。在纯合反义小鼠中观察到肺肿瘤的发生率比半合反义小鼠高两倍，内源性RAR β 2信使水平在转基因肺组织中降低，并在肿瘤中进一步降低，RAR β 4是一种截短的同种型，来源于与RAR β 2相同的转录本，不携带由反义构建体鉴定的序列，并且其信息不受强烈影响。免疫荧光研究表明RAR β在肿瘤中几乎检测不到，但存在于正常组织中。我们得出结论，RAR β 2，但可能不是RAR β 4，在抑制小鼠肺肿瘤发生中起重要作用。
Retinoic acid has been shown to be an anticancer agent, and a growing literature suggests that it is the nuclear retinoic acid receptor beta 2 (RAR beta 2) that is primarily responsible for mediating this effect, at least in some systems, To determine whether partial inactivation of RAR beta 2 would predispose to lung cancer in mice, we generated three transgenic lines expressing antisense sequences. When killed at 13-3/4-18 months of age, 21/36 animals had a total of 43 pulmonary tumors superficially visible upon necropsy, whereas among 23 nontransgenic mice, only 1 had a single visible lung tumor, A twofold higher incidence of lung tumors was seen in homozygous vs, hemizygous antisense mice, The endogenous RAR beta 2 message level was reduced in transgenic lung tissue and further reduced in the tumors, RAR beta 4, a truncated isoform derived from the same transcript as RAR beta 2, does not carry the sequence identified by the antisense construct and its message was not as strongly affected, Immunofluorescence studies showed that RAR beta was virtually undetectable in the tumors, but present in normal tissue, We conclude that RAR beta 2, but probably not RAR beta 4, plays an important role in suppression of murine lung tumorigenesis.