Lack of an additive effect between the deletions of Klf5 and Nkx3-1 in mouse prostatic tumorigenesis.
Lack of an additive effect between the deletions of Klf5 and Nkx3-1 in mouse prostatic tumorigenesis.
复制标题
Klf5 和 Nkx3-1 的缺失在小鼠前列腺肿瘤发生中缺乏相加效应。
DOI：
10.1016/j.jgg.2013.04.005
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Dong,Jin-Tang
中科院分区：
文献类型：
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作者：
Xing,Changsheng;Fu,Xiaoying;Sun,Xiaodong;Dong,Jin-Tang
前列腺癌是工业化国家最常见的恶性肿瘤之一，也是癌症死亡的主要原因。前列腺癌的发生和发展是由一系列遗传和表观遗传事件驱动的，包括激活癌基因的基因放大和使抑癌基因失活的染色体缺失。虽然人类前列腺癌中存在基因扩增，但基因缺失更为常见，并且已发现前列腺癌中大量染色体区域频繁缺失，这表明在前列腺癌的发生过程中，抑癌基因失活比癌基因激活更常见(Knuutila等人，1998,1999；董，2001)。在前列腺癌中最常见的缺失染色体区域中，靶基因如8p21的NKX3-1、10q23的PTEN和16q22的ATBF1已被用不同的方法鉴定(He等人，1997；Li等人，1997；Sun等人，2005)，这些基因的缺失已被证明在小鼠前列腺中诱导和/或促进前列腺癌的发生。例如，在小鼠中，Nkx3-1基因敲除会导致增生和异型增生(Bhatia-Gaur等人，1999；Abdulkadir等人，2002)，并促进前列腺肿瘤的发生(Abate-Shenin等人，2003)，而Pten基因敲除本身就会导致前列腺癌(Wang等人，2003)。因此，基因缺失在前列腺癌的发生中起着因果作用(董，2001)。人类染色体13的q21区域(13q21)的缺失是人类前列腺癌和其他类型的恶性肿瘤中第二常见的缺失(Knuutila等人，1999；董等人，2000；Chen等人，2001；董等人，2001)，KLF5基因被认为是13q21肿瘤抑制基因，因为它集中在13q21缺失(Chen等人，2003)。KLF5已在小鼠模型中被检测到肿瘤抑制活性，包括异种移植模型中KLF5的表达抑制人类前列腺癌细胞系的肿瘤形成(Nakajima等人，2011年)，以及敲除KLF5的小鼠模型中KLF5基因敲除增加细胞增殖并诱导前列腺上皮细胞增殖(数据未显示)，并促进Pten缺失在前列腺癌发生中的作用(数据未显示)。
Prostate cancer is one of the most common malignancies and a leading cause of cancer death in industrialized countries. The development and progression of prostate cancer are driven by a series of genetic and epigenetic events including gene amplification that activates oncogenes and chromosomal deletion that inactivates tumor suppressor genes. Whereas gene amplification occurs in human prostate cancer, gene deletion is more common, and a large number of chromosomal regions have been identified to have frequent deletion in prostate cancer, suggesting that tumor suppressor inactivation is more common than oncogene activation in prostatic carcinogenesis (Knuutila et al., 1998, 1999; Dong, 2001). Among the most frequently deleted chromosomal regions in prostate cancer, target genes such as NKX3-1 from 8p21, PTEN from 10q23 and ATBF1 from 16q22 have been identified by different approaches (He et al., 1997; Li et al., 1997; Sun et al., 2005), and deletion of these genes in mouse prostates has been demonstrated to induce and/or promote prostatic carcinogenesis. For example, knockout of Nkx3-1 in mice induces hyperplasia and dysplasia (Bhatia-Gaur et al., 1999; Abdulkadir et al., 2002) and promotes prostatic tumorigenesis (Abate-Shen et al., 2003), while knockout of Pten alone causes prostatic neoplasia (Wang et al., 2003). Therefore, gene deletion plays a causal role in prostatic carcinogenesis (Dong, 2001).The deletion of the q21 region of human chromosome 13 (13q21) is the second most frequent deletion in human prostate cancer and other types of malignancies (Knuutila et al., 1999; Dong et al., 2000; Chen et al., 2001; Dong, 2001), and the KLF5 gene has been suggested to be the 13q21 tumor suppressor gene because it centers the 13q21 deletion (Chen et al., 2003). A tumor suppressor activity has been detected for KLF5 in mouse models, including xenograft models in which KLF5 expression inhibits the tumorigenesis of human prostate cancer cell lines (Nakajima et al., 2011) and the knockout mouse model in which knockout of Klf5 increases cell proliferation and induces hyperplasia in prostate epithelial cells (data not shown), and promotes the effect of Pten deletion in prostatic carcinogenesis (data not shown).