Declercq Jeroen, Van Dyck Frederik, Braem Caroline V, Van Valckenborgh Isabelle C, Voz Marianne, Wassef Michel, Schoonjans Luc, Van Damme Boudewijn, Fiette Laurence, Van de Ven Wim J M
Laboratory for Molecular Oncology, Department of Human Genetics, K.U. Leuven, Belgium.
Cancer Res. 2005 Jun 1;65(11):4544-53. doi: 10.1158/0008-5472.CAN-04-4041.
Pleomorphic adenoma gene 1 (PLAG1) proto-oncogene overexpression is implicated in various human neoplasias, including salivary gland pleomorphic adenomas. To further assess the oncogenic capacity of PLAG1, two independent PLAG1 transgenic mouse strains were established, PTMS1 and PTMS2, in which activation of PLAG1 overexpression is Cre mediated. Crossbreeding of PTMS1 or PTMS2 mice with MMTV-Cre transgenic mice was done to target PLAG1 overexpression to salivary and mammary glands, in the P1-Mcre/P2-Mcre offspring. With a prevalence of 100% and 6%, respectively, P1-Mcre and P2-Mcre mice developed salivary gland tumors displaying various pleomorphic adenoma features. Moreover, histopathologic analysis of salivary glands of 1-week-old P1-Mcre mice pointed at early tumoral stages in epithelial structures. Malignant characteristics in the salivary gland tumors and frequent lung metastases were found in older tumor-bearing mice. PLAG1 overexpression was shown in all tumors, including early tumoral stages. The tumors revealed an up-regulation of the expression of two distinct, imprinted gene clusters (i.e., Igf2/H19 and Dlk1/Gtl2). With a latency period of about 1 year, 8% of the P2-Mcre mice developed mammary gland tumors displaying similar histopathologic features as the salivary gland tumors. In conclusion, our results establish the strong and apparently direct in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well.
多形性腺瘤基因1（PLAG1）原癌基因的过表达与多种人类肿瘤相关，包括涎腺多形性腺瘤。为了进一步评估PLAG1的致癌能力，建立了两种独立的PLAG1转基因小鼠品系PTMS1和PTMS2，其中PLAG1过表达的激活由Cre介导。将PTMS1或PTMS2小鼠与MMTV-Cre转基因小鼠杂交，以使PLAG1在P1-Mcre/P2-Mcre后代的唾液腺和乳腺中过表达。P1-Mcre和P2-Mcre小鼠分别以100%和6%的发生率发生了具有各种多形性腺瘤特征的涎腺肿瘤。此外，对1周龄P1-Mcre小鼠唾液腺的组织病理学分析表明上皮结构处于肿瘤早期阶段。在老年荷瘤小鼠中发现涎腺肿瘤具有恶性特征且频繁发生肺转移。在所有肿瘤中均显示PLAG1过表达，包括肿瘤早期阶段。这些肿瘤显示出两个不同的印记基因簇（即Igf2/H19和Dlk1/Gtl2）的表达上调。约1年的潜伏期后，8%的P2-Mcre小鼠发生了乳腺肿瘤，其组织病理学特征与涎腺肿瘤相似。总之，我们的结果证实了PLAG1强大且明显直接的体内致瘤能力，并表明转基因小鼠构成了涎腺多形性腺瘤发生以及可能其他腺体肿瘤发生的有价值模型。
